NM_000381.4:c.661-8_661-7dupTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000381.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	NM_000381.4	MANE Select	c.661-8_661-7dupTT		splice_region intron	N/A	NP_000372.1
	MID1	NM_001098624.2		c.661-8_661-7dupTT		splice_region intron	N/A	NP_001092094.1
	MID1	NM_001193277.1		c.661-8_661-7dupTT		splice_region intron	N/A	NP_001180206.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	ENST00000317552.9	TSL:1 MANE Select	c.661-7_661-6insTT		splice_region intron	N/A	ENSP00000312678.4
	MID1	ENST00000380779.5	TSL:1	c.661-7_661-6insTT		splice_region intron	N/A	ENSP00000370156.1
	MID1	ENST00000380780.5	TSL:1	c.661-7_661-6insTT		splice_region intron	N/A	ENSP00000370157.1

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 2734 AN: 45374 Hom.: 140 Cov.: 19

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

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.: 0 Cov.: 0 AF XY: 0.000124 AC XY: 25 AN XY: 200851

⚠️ 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: 52 AN: 14554

East Asian (EAS) AF: 0.000771 AC: 19 AN: 24646

South Asian (SAS) AF: 0.00237 AC: 85 AN: 35918

European-Finnish (FIN) AF: 0.00246 AC: 65 AN: 26465

Middle Eastern (MID) AF: 0.00135 AC: 3 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.

GnomAD4 genome AF: 0.0603 AC: 2735 AN: 45373 Hom.: 140 Cov.: 19 AF XY: 0.0382 AC XY: 344 AN XY: 9011

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: 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: 0.000666 AC: 1 AN: 1502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 51

European-Non Finnish (NFE) AF: 0.000669 AC: 14 AN: 20931

Other (OTH) AF: 0.0468 AC: 27 AN: 577

Alfa AF: 0.00293 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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 v4.9

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

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;