X-10523193-CAAAAAAAA-CAAAAAAAAA

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.661-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 127 hom., 533 hem., cov: 19)

Exomes 𝑓: 0.099 ( 7 hom. 96 hem. )

Consequence

MID1
NM_000381.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

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-CA is Benign according to our data. Variant chrX-10523193-C-CA is described in ClinVar as Benign. ClinVar VariationId is 196261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0820

AC:

3713

AN:

45300

Hom.:

127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.171

Gnomad AMI

AF:

0.00394

Gnomad AMR

AF:

0.0437

Gnomad ASJ

AF:

0.0405

Gnomad EAS

AF:

0.0101

Gnomad SAS

AF:

0.0556

Gnomad FIN

AF:

0.0810

Gnomad MID

AF:

0.0508

Gnomad NFE

AF:

0.0321

Gnomad OTH

AF:

0.0776

GnomAD2 exomes

AF:

0.138

AC:

6132

AN:

44423

AF XY:

0.0135

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.129

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.128

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.0987

AC:

65056

AN:

659239

Hom.:

Cov.:

AF XY:

0.000648

AC XY:

AN XY:

148087

show subpopulations

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

African (AFR)

AF:

0.147

AC:

2239

AN:

15282

American (AMR)

AF:

0.0819

AC:

1607

AN:

19625

Ashkenazi Jewish (ASJ)

AF:

0.0956

AC:

1240

AN:

12975

East Asian (EAS)

AF:

0.0889

AC:

1905

AN:

21430

South Asian (SAS)

AF:

0.0681

AC:

2034

AN:

29888

European-Finnish (FIN)

AF:

0.104

AC:

2436

AN:

23323

Middle Eastern (MID)

AF:

0.0890

AC:

175

AN:

1966

European-Non Finnish (NFE)

AF:

0.0998

AC:

50416

AN:

504988

Other (OTH)

AF:

0.101

AC:

3004

AN:

29762

⚠️ 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: 0.303

Heterozygous variant carriers

4908

9817

14725

19634

24542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1912

3824

5736

7648

9560

<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:

0.0820

AC:

3716

AN:

45299

Hom.:

127

Cov.:

AF XY:

0.0594

AC XY:

533

AN XY:

8979

show subpopulations

African (AFR)

AF:

0.171

AC:

2616

AN:

15318

American (AMR)

AF:

0.0437

AC:

150

AN:

3434

Ashkenazi Jewish (ASJ)

AF:

0.0405

AC:

AN:

1062

East Asian (EAS)

AF:

0.0102

AC:

AN:

1275

South Asian (SAS)

AF:

0.0571

AC:

AN:

964

European-Finnish (FIN)

AF:

0.0810

AC:

121

AN:

1494

Middle Eastern (MID)

AF:

0.0588

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0321

AC:

670

AN:

20874

Other (OTH)

AF:

0.0768

AC:

AN:

573

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

127

255

382

510

637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0304

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 30, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

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

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