Genetic Variant NM_000381.4:c.661-8_661-7delTT (chrX-10523193-CAA-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000381.4(MID1):c.661-8_661-7delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 711,540 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 0.024 ( 0 hom. 0 hem. )

Consequence

MID1
NM_000381.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.00

Publications

3 publications found

Variant links:

Genes affected

MID1 (HGNC:7095): (midline 1) The protein encoded by this gene is a member of the tripartite motif (TRIM) family, also known as the 'RING-B box-coiled coil' (RBCC) subgroup of RING finger proteins. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This protein forms homodimers which associate with microtubules in the cytoplasm. The protein is likely involved in the formation of multiprotein structures acting as anchor points to microtubules. Mutations in this gene have been associated with the X-linked form of Opitz syndrome, which is characterized by midline abnormalities such as cleft lip, laryngeal cleft, heart defects, hypospadias, and agenesis of the corpus callosum. This gene was also the first example of a gene subject to X inactivation in human while escaping it in mouse. Alternative promoter use, alternative splicing and alternative polyadenylation result in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]

MID1 Gene-Disease associations (from GenCC):

X-linked Opitz G/BBB syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

MID1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP6

Variant X-10523193-CAA-C is Benign according to our data. Variant chrX-10523193-CAA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211500.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
MID1	NM_000381.4 link	c.661-8_661-7delTT		splice_region_variant, intron_variant	Intron 2 of 9	ENST00000317552.9	NP_000372.1	O15344-1A0A024RBV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MID1	ENST00000317552.9 link	c.661-8_661-7delTT		splice_region_variant, intron_variant	Intron 2 of 9	1	NM_000381.4	ENSP00000312678.4		O15344-1
MID1	ENST00000380782.6 link	c.661-8_661-7delTT		splice_region_variant, intron_variant	Intron 2 of 9	1		ENSP00000370159.1		O15344-2

Frequencies

GnomAD3 genomes

AF:

0.000330

AC:

AN:

45394

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00338

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000335

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0311

AC:

1382

AN:

44423

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.0485

Gnomad ASJ exome

AF:

0.0267

Gnomad EAS exome

AF:

0.0398

Gnomad FIN exome

AF:

0.0256

Gnomad NFE exome

AF:

0.0272

Gnomad OTH exome

AF:

0.0400

GnomAD4 exome

AF:

0.0244

AC:

16251

AN:

666146

Hom.:

AF XY:

0.00

AC XY:

AN XY:

174846

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0183

AC:

292

AN:

15991

American (AMR)

AF:

0.0230

AC:

446

AN:

19427

Ashkenazi Jewish (ASJ)

AF:

0.0206

AC:

267

AN:

12954

East Asian (EAS)

AF:

0.0168

AC:

363

AN:

21635

South Asian (SAS)

AF:

0.0127

AC:

403

AN:

31647

European-Finnish (FIN)

AF:

0.0158

AC:

377

AN:

23855

Middle Eastern (MID)

AF:

0.0175

AC:

AN:

1995

European-Non Finnish (NFE)

AF:

0.0264

AC:

13403

AN:

508645

Other (OTH)

AF:

0.0222

AC:

665

AN:

29997

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.261

Heterozygous variant carriers

1883

3766

5648

7531

9414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

596

1192

1788

2384

2980

<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:

0.000330

AC:

AN:

45394

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

9008

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000652

AC:

AN:

15345

American (AMR)

AF:

0.00

AC:

AN:

3443

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

1061

East Asian (EAS)

AF:

0.00

AC:

AN:

1285

South Asian (SAS)

AF:

0.00

AC:

AN:

972

European-Finnish (FIN)

AF:

0.00338

AC:

AN:

1480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000335

AC:

AN:

20924

Other (OTH)

AF:

0.00

AC:

AN:

571

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.285

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0129

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 30, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 21, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over