chr14-74356826-C-A

Position:

• chr14-74356826-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018228.3(VRTN):​c.43C>A​(p.Leu15Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VRTN NM_018228.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72

Genes affected

VRTN (HGNC:20223): (vertebrae development associated) Predicted to enable sequence-specific DNA binding activity and transposase activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.17681676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VRTN	NM_018228.3	c.43C>A	p.Leu15Met	missense_variant	2/2	ENST00000256362.5	NP_060698.2
VRTN	XM_011536911.3	c.43C>A	p.Leu15Met	missense_variant	3/3		XP_011535213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VRTN	ENST00000256362.5	c.43C>A	p.Leu15Met	missense_variant	2/2	1	NM_018228.3	ENSP00000256362.4
VRTN	ENST00000557177.1	c.43C>A	p.Leu15Met	missense_variant	3/3	4		ENSP00000452158.1

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

Feb 12, 2024

The c.43C>A (p.L15M) alteration is located in exon 2 (coding exon 1) of the VRTN gene. This alteration results from a C to A substitution at nucleotide position 43, causing the leucine (L) at amino acid position 15 to be replaced by a methionine (M). 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	0.27
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	0.031
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.092
Sift	Benign	0.049	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.83	.;P
Vest4		0.32
MutPred		0.28		Gain of catalytic residue at V11 (P = 0.0265);Gain of catalytic residue at V11 (P = 0.0265);
MVP		0.16
MPC		0.58
ClinPred		0.74	D
GERP RS		3.1
Varity_R		0.15
gMVP		0.84

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: chr14-74823529;