rs750035706

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM4PP5_Very_Strong

The NM_024298.5(MBOAT7):c.758_778delAGTGCGGCTGCATTGCCGCCG(p.Glu253_Ala259del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000525 in 1,579,556 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

MBOAT7
NM_024298.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.56

Publications

1 publications found

Variant links:

Genes affected

MBOAT7 (HGNC:15505): (membrane bound O-acyltransferase domain containing 7) This gene encodes a member of the membrane-bound O-acyltransferases family of integral membrane proteins that have acyltransferase activity. The encoded protein is a lysophosphatidylinositol acyltransferase that has specificity for arachidonoyl-CoA as an acyl donor. This protein is involved in the reacylation of phospholipids as part of the phospholipid remodeling pathway known as the Land cycle. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2009]

MBOAT7 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 57
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MBOAT7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_024298.5.

PP5

Variant 19-54180848-CCGGCGGCAATGCAGCCGCACT-C is Pathogenic according to our data. Variant chr19-54180848-CCGGCGGCAATGCAGCCGCACT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 268112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBOAT7	NM_024298.5 link	c.758_778delAGTGCGGCTGCATTGCCGCCG	p.Glu253_Ala259del	disruptive_inframe_deletion	Exon 6 of 8	ENST00000245615.6	NP_077274.3	Q96N66-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBOAT7	ENST00000245615.6 link	c.758_778delAGTGCGGCTGCATTGCCGCCG	p.Glu253_Ala259del	disruptive_inframe_deletion	Exon 6 of 8	1	NM_024298.5	ENSP00000245615.1		Q96N66-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

182932

AF XY:

0.0000301

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000574

AC:

AN:

1427354

Hom.:

AF XY:

0.0000622

AC XY:

AN XY:

707032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33150

American (AMR)

AF:

0.00

AC:

AN:

37782

Ashkenazi Jewish (ASJ)

AF:

0.0000393

AC:

AN:

25414

East Asian (EAS)

AF:

0.00

AC:

AN:

38614

South Asian (SAS)

AF:

0.000146

AC:

AN:

82024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5370

European-Non Finnish (NFE)

AF:

0.0000619

AC:

AN:

1097818

Other (OTH)

AF:

0.0000169

AC:

AN:

59238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.416

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 57

Pathogenic:5

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual disability 57 (MIM#617188). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0213 - In-frame deletion in a non-repetitive region that has moderate conservation. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 5 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated catalytic acyltransferase domain (PMID: 27616480). (I) 0705 - No comparable in-frame deletion variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in five consanguineous families with neurodevelopmental disorders. It should be noted that all the families are from Pakistan, with four of the families originating from the Khyber Pakhtunkhwa Province (PMIDs: 27616480, 31852446, 33335874). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been demonstrated to be homozygous in affected individuals only, with unaffected individuals shown to be heterozygous for the variant (PMID: 31852446). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant was co-segregated with Mental retardation, autosomal recessive 57 in multiple affected family members with additional meioses meeting moderate evidence levels (PMID: 31852446, 27616480). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 31852446, 27616480). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000272). Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function(PM4_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 26, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MBOAT7 c.758_778del21 (p.Glu253_Ala259del) results in an in-frame deletion that is predicted to remove seven amino acids from the encoded protein. The variant allele was found at a frequency of 2.2e-05 in 182932 control chromosomes. c.758_778del21 has been reported in the literature in multiple homozygous individuals affected with Mental Retardation, Autosomal Recessive 57 and has been reported as a founder mutation in the Pakistani population (e.g. Khan_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31852446). ClinVar contains an entry for this variant (Variation ID: 268112). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 18, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Sep 25, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame deletion of 7 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31852446, 27616480, 33335874) -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MBOAT7: PP1:Strong, PM1, PM4, PM2:Supporting, PM3:Supporting, PP4 -

Inborn genetic diseases

Pathogenic:1

Jul 15, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.758_778del21 (p.E253_A259del) alteration, located in exon 6 (coding exon 5) of the MBOAT7 gene, results from an in-frame deletion of 21 nucleotides between nucleotide positions c.758 and c.778. This results in the deletion of 7 amino acids from codons 253 to 259. Based on data from gnomAD, this alteration has an overall frequency of 0.002% (5/214278) total alleles studied. The highest observed frequency was 0.016% (4/25456) of South Asian alleles. This alteration has been reported in multiple patients from consanguineous families with moderate to severe neurodevelopmental disorders (Johansen, 2016; Khan, 2019; Sun, 2020). There is evidence to suggest that it is a founder mutation in the Pakistani population (Khan, 2019; Sun, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.6

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over