Genetic Variant TMEM37:p.Phe21Leu (chr2-119436928-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_183240.3(TMEM37):c.61T>C(p.Phe21Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM37
NM_183240.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.30

Variant links:

Genes affected

TMEM37 (HGNC:18216): (transmembrane protein 37) Predicted to enable calcium channel activity and voltage-gated ion channel activity. Predicted to be involved in calcium ion transmembrane transport and regulation of ion transmembrane transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM37 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26789087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM37	NM_183240.3 link	c.61T>C	p.Phe21Leu	missense_variant	Exon 2 of 2	ENST00000306406.5	NP_899063.2	Q8WXS4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM37	ENST00000306406.5 link	c.61T>C	p.Phe21Leu	missense_variant	Exon 2 of 2	1	NM_183240.3	ENSP00000303148.4	Q8WXS4
TMEM37	ENST00000409826.1 link	c.97T>C	p.Phe33Leu	missense_variant	Exon 2 of 2	3		ENSP00000387015.1	E7EMC0
TMEM37	ENST00000417645.1 link	c.78T>C	p.Pro26Pro	synonymous_variant	Exon 2 of 2	3		ENSP00000400770.1	C9J1Q8
TMEM37	ENST00000465296.1 link	n.201T>C		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251028

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.61T>C (p.F21L) alteration is located in exon 2 (coding exon 2) of the TMEM37 gene. This alteration results from a T to C substitution at nucleotide position 61, causing the phenylalanine (F) at amino acid position 21 to be replaced by a leucine (L). 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

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;D

Eigen

Benign

0.12

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.8

.;M

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Benign

0.24

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.096

.;B

Vest4

0.65

MutPred

0.43

.;Gain of MoRF binding (P = 0.1093);

MVP

0.18

MPC

1.2

ClinPred

0.98

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.87

gMVP

0.59

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