chr4-140395849-T-A

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

1
18

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]

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 Protein UniProt
CLGNNM_004362.3 linkuse as main transcriptc.1119A>T p.Arg373Ser missense_variant 10/15 ENST00000325617.10 NP_004353.1
CLGNNM_001130675.2 linkuse as main transcriptc.1119A>T p.Arg373Ser missense_variant 11/16 NP_001124147.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLGNENST00000325617.10 linkuse as main transcriptc.1119A>T p.Arg373Ser missense_variant 10/151 NM_004362.3 ENSP00000326699 P1O14967-1
CLGNENST00000414773.5 linkuse as main transcriptc.1119A>T p.Arg373Ser missense_variant 11/161 ENSP00000392782 P1O14967-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152084
Hom.:
0
Cov.:
31
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:
19
AN:
199508
Hom.:
0
AF XY:
0.000121
AC XY:
13
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:
78
AN:
1393194
Hom.:
0
Cov.:
31
AF XY:
0.0000580
AC XY:
40
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:
8
AN:
152084
Hom.:
0
Cov.:
31
AF XY:
0.0000673
AC XY:
5
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.:
0
Bravo
AF:
0.0000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9

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 submitterclinical testingAmbry GeneticsJan 02, 2024The 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
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
17
DANN
Benign
0.97
DEOGEN2
Benign
0.24
T;T
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.81
T;.
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.073
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.070
N;N
MutationTaster
Benign
0.93
D;D;D
PrimateAI
Benign
0.26
T
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
T
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.

Other links and lift over

dbSNP: rs377332621; hg19: chr4-141317003; API