X-10523193-CAAAAAAAA-CAAAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000381.4(MID1):c.661-8_661-7dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 140 hom., 344 hem., cov: 19)

Exomes 𝑓: 0.0042 ( 0 hom. 25 hem. )

Consequence

MID1
NM_000381.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

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 -16 ACMG points.

BP6

Variant X-10523193-C-CAA is Benign according to our data. Variant chrX-10523193-C-CAA is described in ClinVar as Benign. ClinVar VariationId is 196260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0603

AC:

2734

AN:

45374

Hom.:

140

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0299

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000666

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000669

Gnomad OTH

AF:

0.0473

GnomAD2 exomes

AF:

0.0154

AC:

682

AN:

44423

AF XY:

0.00427

show subpopulations

Gnomad AFR exome

AF:

0.0785

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.00712

Gnomad FIN exome

AF:

0.00788

Gnomad NFE exome

AF:

0.00773

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.00419

AC:

3058

AN:

730559

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

200851

show subpopulations

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

African (AFR)

AF:

0.0584

AC:

954

AN:

16326

American (AMR)

AF:

0.00552

AC:

119

AN:

21568

Ashkenazi Jewish (ASJ)

AF:

0.00357

AC:

AN:

14554

East Asian (EAS)

AF:

0.000771

AC:

AN:

24646

South Asian (SAS)

AF:

0.00237

AC:

AN:

35918

European-Finnish (FIN)

AF:

0.00246

AC:

AN:

26465

Middle Eastern (MID)

AF:

0.00135

AC:

AN:

2220

European-Non Finnish (NFE)

AF:

0.00277

AC:

1541

AN:

555865

Other (OTH)

AF:

0.00667

AC:

220

AN:

32997

⚠️ 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: 0.304

Heterozygous variant carriers

239

478

717

956

1195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.0603

AC:

2735

AN:

45373

Hom.:

140

Cov.:

AF XY:

0.0382

AC XY:

344

AN XY:

9011

show subpopulations

African (AFR)

AF:

0.169

AC:

2590

AN:

15307

American (AMR)

AF:

0.0299

AC:

103

AN:

3446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1063

East Asian (EAS)

AF:

0.00

AC:

AN:

1277

South Asian (SAS)

AF:

0.00

AC:

AN:

965

European-Finnish (FIN)

AF:

0.000666

AC:

AN:

1502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000669

AC:

AN:

20931

Other (OTH)

AF:

0.0468

AC:

AN:

577

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

181

271

362

452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00293

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 01, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 25, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 12, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2021

GeneDx

Significance: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 (auto)

(source)

Splicing

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