X-10449435-T-A

Variant names:

• chrX-10449435-T-A
• rs757315836
• NM_000381.4:c.1937A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000381.4(MID1):​c.1937A>T​(p.Lys646Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000893 in 111,970 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: MID1 NM_000381.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.69

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MID1	NM_000381.4	c.1937A>T	p.Lys646Met	missense_variant	Exon 10 of 10	ENST00000317552.9	NP_000372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MID1	ENST00000317552.9	c.1937A>T	p.Lys646Met	missense_variant	Exon 10 of 10	1	NM_000381.4	ENSP00000312678.4
MID1	ENST00000380782	c.*178A>T		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000370159.1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111970 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34132

Gnomad AFR AF: 0.0000325

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111970 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34132

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;T;T;T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;.;.;.;.;.
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D;D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.41
MutPred		0.57		Loss of methylation at K646 (P = 2e-04);Loss of methylation at K646 (P = 2e-04);Loss of methylation at K646 (P = 2e-04);Loss of methylation at K646 (P = 2e-04);Loss of methylation at K646 (P = 2e-04);Loss of methylation at K646 (P = 2e-04);
MVP		0.84
MPC		2.2
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.77

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: rs757315836; hg19: chrX-10417475;