Variant 7-135164962-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018295.5(TMEM140):c.521G>A(p.Arg174Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,451,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TMEM140
NM_018295.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

Variant links:

Genes affected

TMEM140 (HGNC:21870): (transmembrane protein 140) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM140 links:

CYREN (HGNC:22432): (cell cycle regulator of NHEJ) Involved in double-strand break repair via nonhomologous end joining and negative regulation of double-strand break repair via nonhomologous end joining. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CYREN links:

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ACMG classification

Classification made for transcript

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=0.086830914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM140	NM_018295.5 linkuse as main transcript	c.521G>A	p.Arg174Lys	missense_variant	2/2	ENST00000275767.3
CYREN	NM_001305630.2 linkuse as main transcript	c.174+3787C>T		intron_variant
CYREN	XM_017012595.2 linkuse as main transcript	c.*40+2770C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM140	ENST00000275767.3 linkuse as main transcript	c.521G>A	p.Arg174Lys	missense_variant	2/2	1	NM_018295.5	P1
CYREN	ENST00000459937.5 linkuse as main transcript	n.356+3787C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1451828

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000362

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Oct 05, 2023

The c.521G>A (p.R174K) alteration is located in exon 2 (coding exon 1) of the TMEM140 gene. This alteration results from a G to A substitution at nucleotide position 521, causing the arginine (R) at amino acid position 174 to be replaced by a lysine (K). 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

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.3

DANN

Benign

0.65

DEOGEN2

Benign

0.0049

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.24

M_CAP

Benign

0.0040

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.3

REVEL

Benign

0.048

Sift

Benign

0.12

Sift4G

Pathogenic

0.0

Polyphen

0.035

Vest4

0.17

MutPred

0.39

Gain of ubiquitination at R174 (P = 0.0131);

MVP

0.014

MPC

0.17

ClinPred

0.15

GERP RS

3.1

Varity_R

0.095

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over