X-10523193-CAAAAAAAA-CAAAAAAAAAAA

Variant names:

• chrX-10523193-C-CAAA
• rs375668839
• NM_000381.4:c.661-9_661-7dupTTT

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.661-9_661-7dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., 10 hem., cov: 19)
  • Exomes 𝑓: 0.00032 (0 hom. 2 hem.)
• Consequence: MID1 NM_000381.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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-C-CAAA is Benign according to our data. Variant chrX-10523193-C-CAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 2659977.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00172 (78/45440) while in subpopulation AFR AF = 0.00495 (76/15367). AF 95% confidence interval is 0.00405. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 78 AN: 45441 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00495

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: 0.0169

Gnomad NFE AF: 0.0000478

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000320 AC: 237 AN: 739931 Hom.: 0 Cov.: 0 AF XY: 0.00000972 AC XY: 2 AN XY: 205661

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

African (AFR) AF: 0.00535 AC: 91 AN: 17006

American (AMR) AF: 0.000503 AC: 11 AN: 21851

Ashkenazi Jewish (ASJ) AF: 0.000204 AC: 3 AN: 14729

East Asian (EAS) AF: 0.0000401 AC: 1 AN: 24928

South Asian (SAS) AF: 0.000327 AC: 12 AN: 36673

European-Finnish (FIN) AF: 0.000186 AC: 5 AN: 26834

Middle Eastern (MID) AF: 0.000444 AC: 1 AN: 2251

European-Non Finnish (NFE) AF: 0.000165 AC: 93 AN: 562187

Other (OTH) AF: 0.000598 AC: 20 AN: 33472

⚠️ 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: 0.00172 AC: 78 AN: 45440 Hom.: 0 Cov.: 19 AF XY: 0.00111 AC XY: 10 AN XY: 9026

African (AFR) AF: 0.00495 AC: 76 AN: 15367

American (AMR) AF: 0.00 AC: 0 AN: 3449

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1063

East Asian (EAS) AF: 0.00 AC: 0 AN: 1277

South Asian (SAS) AF: 0.00 AC: 0 AN: 965

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1504

Middle Eastern (MID) AF: 0.0196 AC: 1 AN: 51

European-Non Finnish (NFE) AF: 0.0000478 AC: 1 AN: 20933

Other (OTH) AF: 0.00 AC: 0 AN: 577

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MID1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs375668839; hg19: chrX-10491233;