rs7391874

chrX-10567050-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000381.4(MID1):c.498G>A(p.Pro166=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,209,747 control chromosomes in the GnomAD database, including 60 homozygotes. There are 713 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 0.0038 (5 hom., 144 hem., cov: 22)
  • Exomes 𝑓: 0.0021 (55 hom. 569 hem.)
• Consequence: MID1 NM_000381.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.37

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant X-10567050-C-T is Benign according to our data. Variant chrX-10567050-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MID1	NM_000381.4	c.498G>A	p.Pro166=	synonymous_variant	2/10	ENST00000317552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MID1	ENST00000317552.9	c.498G>A	p.Pro166=	synonymous_variant	2/10	1	NM_000381.4	P1
	ENST00000706950.1	c.*500G>A		3_prime_UTR_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 419 AN: 111454 Hom.: 5 Cov.: 22 AF XY: 0.00428 AC XY: 144 AN XY: 33654

Gnomad AFR AF: 0.00105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00763

Gnomad SAS AF: 0.000758

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00467

GnomAD3 exomes AF: 0.00974 AC: 1786 AN: 183366 Hom.: 50 AF XY: 0.00630 AC XY: 427 AN XY: 67826

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.0598

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00577

Gnomad SAS exome AF: 0.000314

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.00795

GnomAD4 exome AF: 0.00209 AC: 2290 AN: 1098240 Hom.: 55 Cov.: 32 AF XY: 0.00156 AC XY: 569 AN XY: 363594

Gnomad4 AFR exome AF: 0.000606

Gnomad4 AMR exome AF: 0.0535

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00358

Gnomad4 SAS exome AF: 0.000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.00256

GnomAD4 genome AF: 0.00378 AC: 422 AN: 111507 Hom.: 5 Cov.: 22 AF XY: 0.00427 AC XY: 144 AN XY: 33717

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.0330

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00766

Gnomad4 SAS AF: 0.000760

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00461

Alfa AF: 0.00135 Hom.: 5

Bravo AF: 0.00638

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2016

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. -

MID1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

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

X-linked Opitz G/BBB syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	6.5
Dann	Benign	0.76

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: rs7391874; hg19: chrX-10535090;