chr14-105529351-T-A

Position:

• chr14-105529351-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_025268.4(TMEM121):​c.517T>A​(p.Ser173Thr) 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 Likely benign (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: TMEM121 NM_025268.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.20

Genes affected

TMEM121 (HGNC:20511): (transmembrane protein 121) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03686014).
• BP6: Variant 14-105529351-T-A is Benign according to our data. Variant chr14-105529351-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2569563.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM121	NM_025268.4	c.517T>A	p.Ser173Thr	missense_variant	2/2	ENST00000392519.7
TMEM121	NM_001331238.2	c.517T>A	p.Ser173Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM121	ENST00000392519.7	c.517T>A	p.Ser173Thr	missense_variant	2/2	1	NM_025268.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.034	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.21	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.092
Sift	Benign	0.68	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.0	B;B
Vest4		0.091
MutPred		0.21		Loss of disorder (P = 0.0644);Loss of disorder (P = 0.0644);
MVP		0.11
MPC		1.1
ClinPred		0.099	T
GERP RS		0.36
Varity_R		0.043
gMVP		0.38

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: chr14-105995688; COSMIC: COSV105328740; COSMIC: COSV105328740;