rs41303167

chrX-10566960-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000381.4(MID1):c.588C>G(p.Ala196=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,210,045 control chromosomes in the GnomAD database, including 3 homozygotes. There are 884 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., 67 hem., cov: 22)
  • Exomes 𝑓: 0.0022 (3 hom. 817 hem.)
• Consequence: MID1 NM_000381.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.56

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-10566960-G-C is Benign according to our data. Variant chrX-10566960-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 195070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-10566960-G-C is described in Lovd as [Benign]. Variant chrX-10566960-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00188 (210/111841) while in subpopulation NFE AF= 0.00305 (162/53121). AF 95% confidence interval is 0.00267. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 67 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MID1	NM_000381.4	c.588C>G	p.Ala196=	synonymous_variant	2/10	ENST00000317552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MID1	ENST00000317552.9	c.588C>G	p.Ala196=	synonymous_variant	2/10	1	NM_000381.4	P1
	ENST00000706950.1	c.*590C>G		3_prime_UTR_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 210 AN: 111788 Hom.: 0 Cov.: 22 AF XY: 0.00197 AC XY: 67 AN XY: 33962

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000379

Gnomad ASJ AF: 0.00602

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00229

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.00305

Gnomad OTH AF: 0.00264

GnomAD3 exomes AF: 0.00171 AC: 313 AN: 183453 Hom.: 1 AF XY: 0.00169 AC XY: 115 AN XY: 67891

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.00281

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000419

Gnomad FIN exome AF: 0.00225

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00224 AC: 2463 AN: 1098204 Hom.: 3 Cov.: 31 AF XY: 0.00225 AC XY: 817 AN XY: 363562

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.000511

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000425

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00188 AC: 210 AN: 111841 Hom.: 0 Cov.: 22 AF XY: 0.00197 AC XY: 67 AN XY: 34025

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.000378

Gnomad4 ASJ AF: 0.00602

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00229

Gnomad4 NFE AF: 0.00305

Gnomad4 OTH AF: 0.00261

Alfa AF: 0.00276 Hom.: 21

Bravo AF: 0.00155

EpiCase AF: 0.00354

EpiControl AF: 0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2016	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

MID1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	13
Dann	Benign	0.68

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: rs41303167; hg19: chrX-10535000;