Variant 4-140395849-T-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_004362.3(CLGN):c.1119A>T(p.Arg373Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000557 in 1,545,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

CLGN
NM_004362.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0140

Variant links:

Genes affected

CLGN (HGNC:2060): (calmegin) Calmegin is a testis-specific endoplasmic reticulum chaperone protein. CLGN may play a role in spermatogeneisis and infertility. [provided by RefSeq, Jul 2008]

CLGN links:

Genome browser will be placed here

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=0.07336226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLGN	NM_004362.3 linkuse as main transcript	c.1119A>T	p.Arg373Ser	missense_variant	10/15	ENST00000325617.10
CLGN	NM_001130675.2 linkuse as main transcript	c.1119A>T	p.Arg373Ser	missense_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLGN	ENST00000325617.10 linkuse as main transcript	c.1119A>T	p.Arg373Ser	missense_variant	10/15	1	NM_004362.3	P1	O14967-1
CLGN	ENST00000414773.5 linkuse as main transcript	c.1119A>T	p.Arg373Ser	missense_variant	11/16	1		P1	O14967-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000952

AC:

AN:

199508

Hom.:

AF XY:

0.000121

AC XY:

AN XY:

107542

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000626

Gnomad NFE exome

AF:

0.0000719

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000560

AC:

AN:

1393194

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

689296

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:

0.000919

Gnomad4 NFE exome

AF:

0.0000249

Gnomad4 OTH exome

AF:

0.0000696

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000476

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

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 02, 2024

The c.1119A>T (p.R373S) alteration is located in exon 11 (coding exon 9) of the CLGN gene. This alteration results from a A to T substitution at nucleotide position 1119, causing the arginine (R) at amino acid position 373 to be replaced by a serine (S). 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

0.22

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.81

T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.070

N;N

MutationTaster

Benign

0.93

D;D;D

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.092

Sift

Benign

0.38

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0090

B;B

Vest4

0.17

MutPred

0.56

Gain of ubiquitination at K369 (P = 0.0337);Gain of ubiquitination at K369 (P = 0.0337);

MVP

0.32

MPC

0.11

ClinPred

0.061

GERP RS

-1.5

Varity_R

0.19

gMVP

0.40

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