Variant 14-105529705-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025268.4(TMEM121):c.871A>C(p.Asn291His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,525,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

TMEM121
NM_025268.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

Variant links:

Genes affected

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

TMEM121 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025719792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM121	NM_025268.4 linkuse as main transcript	c.871A>C	p.Asn291His	missense_variant	2/2	ENST00000392519.7	NP_079544.1	Q9BTD3
TMEM121	NM_001331238.2 linkuse as main transcript	c.871A>C	p.Asn291His	missense_variant	2/2		NP_001318167.1	Q9BTD3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM121	ENST00000392519.7 linkuse as main transcript	c.871A>C	p.Asn291His	missense_variant	2/2	1	NM_025268.4	ENSP00000376304.2		Q9BTD3

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

138776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000311

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000813

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:

0.000227

Gnomad OTH

AF:

0.00153

GnomAD3 exomes

AF:

0.000457

AC:

AN:

124720

Hom.:

AF XY:

0.000406

AC XY:

AN XY:

68916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000330

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.000236

AC:

327

AN:

1386212

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

151

AN XY:

684590

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000246

Gnomad4 OTH exome

AF:

0.000190

GnomAD4 genome

AF:

0.000223

AC:

AN:

138846

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

67908

show subpopulations

Gnomad4 AFR

AF:

0.0000310

Gnomad4 AMR

AF:

0.000812

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000227

Gnomad4 OTH

AF:

0.00152

Alfa

AF:

0.0000769

Hom.:

Bravo

AF:

0.000253

ExAC

AF:

0.000138

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.871A>C (p.N291H) alteration is located in exon 2 (coding exon 1) of the TMEM121 gene. This alteration results from a A to C substitution at nucleotide position 871, causing the asparagine (N) at amino acid position 291 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.035

T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.39

.;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.040

N;N

REVEL

Benign

0.16

Sift

Benign

0.28

T;T

Sift4G

Benign

0.49

T;T

Polyphen

0.0

B;B

Vest4

0.21

MutPred

0.094

Loss of solvent accessibility (P = 0.0595);Loss of solvent accessibility (P = 0.0595);

MVP

0.10

MPC

2.4

ClinPred

0.17

GERP RS

1.5

Varity_R

0.082

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over