chrX-10523193-CA-C

Variant names:

• chrX-10523193-CA-C
• rs375668839
• NM_000381.4:c.661-7delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000381.4(MID1):​c.661-7delT 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 0.0099 (1 hom., 45 hem., cov: 19)
  • Exomes 𝑓: 0.15 (0 hom. 36 hem.)
• Consequence: MID1 NM_000381.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.00
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant X-10523193-CA-C is Benign according to our data. Variant chrX-10523193-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1205954.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00989 (449/45384) while in subpopulation AFR AF = 0.0138 (212/15362). AF 95% confidence interval is 0.0123. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 45 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MID1	NM_000381.4	c.661-7delT		splice_region_variant, intron_variant	Intron 2 of 9	ENST00000317552.9	NP_000372.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 449 AN: 45385 Hom.: 1 Cov.: 19

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0512

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.0217

Gnomad EAS AF: 0.00390

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.00560

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.207 AC: 9208 AN: 44423 AF XY: 0.000712

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.211

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.151 AC: 91779 AN: 606018 Hom.: 0 Cov.: 0 AF XY: 0.000299 AC XY: 36 AN XY: 120394

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

African (AFR) AF: 0.110 AC: 1658 AN: 15012

American (AMR) AF: 0.131 AC: 2322 AN: 17793

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 1557 AN: 11551

East Asian (EAS) AF: 0.140 AC: 2635 AN: 18841

South Asian (SAS) AF: 0.0930 AC: 2491 AN: 26777

European-Finnish (FIN) AF: 0.133 AC: 2780 AN: 20942

Middle Eastern (MID) AF: 0.133 AC: 237 AN: 1780

European-Non Finnish (NFE) AF: 0.159 AC: 74000 AN: 466195

Other (OTH) AF: 0.151 AC: 4099 AN: 27127

⚠️ 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.

GnomAD4 genome AF: 0.00989 AC: 449 AN: 45384 Hom.: 1 Cov.: 19 AF XY: 0.00500 AC XY: 45 AN XY: 8996

African (AFR) AF: 0.0138 AC: 212 AN: 15362

American (AMR) AF: 0.00785 AC: 27 AN: 3441

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 23 AN: 1060

East Asian (EAS) AF: 0.00392 AC: 5 AN: 1274

South Asian (SAS) AF: 0.0124 AC: 12 AN: 964

European-Finnish (FIN) AF: 0.0200 AC: 30 AN: 1502

Middle Eastern (MID) AF: 0.0784 AC: 4 AN: 51

European-Non Finnish (NFE) AF: 0.00560 AC: 117 AN: 20900

Other (OTH) AF: 0.0104 AC: 6 AN: 576

Alfa AF: 0.0305 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

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)

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

Other links and lift over

dbSNP: rs375668839; hg19: chrX-10491233; COSMIC: COSV58195339;