X-107841062-T-A

Position:

• chrX-107841062-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012216.4(MID2):​c.397T>A​(p.Ser133Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MID2 NM_012216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

Genes affected

MID2 (HGNC:7096): (midline 2) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. 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. The protein localizes to microtubular structures in the cytoplasm. Alternate splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20032471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MID2	NM_012216.4	c.397T>A	p.Ser133Thr	missense_variant	2/10	ENST00000262843.11	NP_036348.2
MID2	NM_001382751.1	c.337T>A	p.Ser113Thr	missense_variant	2/10		NP_001369680.1
MID2	NM_052817.3	c.397T>A	p.Ser133Thr	missense_variant	2/10		NP_438112.2
MID2	NM_001382752.1	c.337T>A	p.Ser113Thr	missense_variant	2/10		NP_001369681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MID2	ENST00000262843.11	c.397T>A	p.Ser133Thr	missense_variant	2/10	1	NM_012216.4	ENSP00000262843
MID2	ENST00000443968.2	c.397T>A	p.Ser133Thr	missense_variant	2/10	1		ENSP00000413976	P1
MID2	ENST00000451923.1	c.337T>A	p.Ser113Thr	missense_variant	2/2	3		ENSP00000410730

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 19, 2022

Variant summary: MID2 c.397T>A (p.Ser133Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 183149 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.397T>A in individuals affected with Intellectual Disability, X-Linked 101 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.021	T;T;.
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.1	.;L;L
MutationTaster	Benign	0.68	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.068	T;T;T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.35, 0.016	.;B;B
Vest4		0.041, 0.095
MutPred		0.14		.;Loss of phosphorylation at S133 (P = 0.0592);Loss of phosphorylation at S133 (P = 0.0592);
MVP		0.83
MPC		0.41
ClinPred		0.23	T
GERP RS		5.9
Varity_R		0.20
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107084292;