X-10523193-CAA-C

Variant names:

• chrX-10523193-CAA-C
• rs375668839
• NM_000381.4:c.661-8_661-7delTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant X-10523193-CAA-C is Benign according to our data. Variant chrX-10523193-CAA-C is described in ClinVar as [Likely_benign]. Clinvar id is 211500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00033 (15/45394) while in subpopulation NFE AF = 0.000335 (7/20924). AF 95% confidence interval is 0.000156. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position FAILED quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000330 AC: 15 AN: 45394 Hom.: 0 Cov.: 19

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

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.: 0 AF XY: 0.00 AC XY: 0 AN XY: 174846

Gnomad4 AFR exome AF: 0.0183 AC: 292 AN: 15991

Gnomad4 AMR exome AF: 0.0230 AC: 446 AN: 19427

Gnomad4 ASJ exome AF: 0.0206 AC: 267 AN: 12954

Gnomad4 EAS exome AF: 0.0168 AC: 363 AN: 21635

Gnomad4 SAS exome AF: 0.0127 AC: 403 AN: 31647

Gnomad4 FIN exome AF: 0.0158 AC: 377 AN: 23855

Gnomad4 NFE exome AF: 0.0264 AC: 13403 AN: 508645

Gnomad4 Remaining exome AF: 0.0222 AC: 665 AN: 29997

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

GnomAD4 genome AF: 0.000330 AC: 15 AN: 45394 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 9008

Gnomad4 AFR AF: 0.0000652 AC: 0.0000651678 AN: 0.0000651678

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00189 AC: 0.00188501 AN: 0.00188501

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00338 AC: 0.00337838 AN: 0.00337838

Gnomad4 NFE AF: 0.000335 AC: 0.000334544 AN: 0.000334544

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

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

Alfa AF: 0.0129 Hom.: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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
Mutation Taster		=100/0	polymorphism

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

LitVar

Other links and lift over

dbSNP: rs375668839; hg19: chrX-10491233;