chr4-140398867-C-A

Position:

• chr4-140398867-C-A

Variant summary

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

The NM_004362.3(CLGN):​c.868G>T​(p.Val290Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V290I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLGN NM_004362.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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.868G>T	p.Val290Phe	missense_variant	8/15	ENST00000325617.10	NP_004353.1
CLGN	NM_001130675.2	c.868G>T	p.Val290Phe	missense_variant	9/16		NP_001124147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLGN	ENST00000325617.10	c.868G>T	p.Val290Phe	missense_variant	8/15	1	NM_004362.3	ENSP00000326699	P1
CLGN	ENST00000414773.5	c.868G>T	p.Val290Phe	missense_variant	9/16	1		ENSP00000392782	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Mar 20, 2024

The c.868G>T (p.V290F) alteration is located in exon 9 (coding exon 7) of the CLGN gene. This alteration results from a G to T substitution at nucleotide position 868, causing the valine (V) at amino acid position 290 to be replaced by a phenylalanine (F). 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	0.11
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	0.000074	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.22
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.83	P;P
Vest4		0.39
MutPred		0.25		Loss of glycosylation at K291 (P = 0.0281);Loss of glycosylation at K291 (P = 0.0281);
MVP		0.78
MPC		0.26
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.59
gMVP		0.49

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: chr4-141320021;