chr4-140393863-C-T

Position:

• chr4-140393863-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004362.3(CLGN):​c.1328G>A​(p.Gly443Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLGN NM_004362.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLGN	NM_004362.3	c.1328G>A	p.Gly443Asp	missense_variant	11/15	ENST00000325617.10	NP_004353.1
CLGN	NM_001130675.2	c.1328G>A	p.Gly443Asp	missense_variant	12/16		NP_001124147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLGN	ENST00000325617.10	c.1328G>A	p.Gly443Asp	missense_variant	11/15	1	NM_004362.3	ENSP00000326699	P1
CLGN	ENST00000414773.5	c.1328G>A	p.Gly443Asp	missense_variant	12/16	1		ENSP00000392782	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.1328G>A (p.G443D) alteration is located in exon 12 (coding exon 10) of the CLGN gene. This alteration results from a G to A substitution at nucleotide position 1328, causing the glycine (G) at amino acid position 443 to be replaced by an aspartic acid (D). 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	Uncertain	0.54
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.076	T;T
Polyphen		0.97	D;D
Vest4		0.54
MutPred		0.64		Loss of MoRF binding (P = 0.0319);Loss of MoRF binding (P = 0.0319);
MVP		0.80
MPC		0.41
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.32
gMVP		0.81

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.

Other links and lift over

hg19: chr4-141315017;