Variant rs750035706 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_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. 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:7

Conservation

PhyloP100: 5.56

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 268112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-54180848-CCGGCGGCAATGCAGCCGCACT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBOAT7	NM_024298.5 linkuse as main transcript	c.758_778delAGTGCGGCTGCATTGCCGCCG	p.Glu253_Ala259del	disruptive_inframe_deletion	6/8	ENST00000245615.6	NP_077274.3	Q96N66-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBOAT7	ENST00000245615.6 linkuse as main transcript	c.758_778delAGTGCGGCTGCATTGCCGCCG	p.Glu253_Ala259del	disruptive_inframe_deletion	6/8	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

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

182932

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

99710

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 SAS exome

AF:

0.000157

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000393

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000146

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000619

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 57

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	MBOAT7: PP1:Strong, PM1, PM4, PM2:Supporting, PM3:Supporting, PP4 -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2022

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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