14-74357180-G-T

Variant names:

• chr14-74357180-G-T
• rs773509797
• NM_018228.3:c.397G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018228.3(VRTN):​c.397G>T​(p.Val133Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,450,342 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V133M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: VRTN NM_018228.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.91
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018228.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRTN	NM_018228.3	MANE Select	c.397G>T	p.Val133Leu	missense	Exon 2 of 2	NP_060698.2	Q9H8Y1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRTN	ENST00000256362.5	TSL:1 MANE Select	c.397G>T	p.Val133Leu	missense	Exon 2 of 2	ENSP00000256362.4	Q9H8Y1
	VRTN	ENST00000925859.1		c.397G>T	p.Val133Leu	missense	Exon 2 of 2	ENSP00000595918.1
	VRTN	ENST00000925860.1		c.397G>T	p.Val133Leu	missense	Exon 3 of 3	ENSP00000595919.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247540 AF XY: 0.00000746

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1450342 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 720132

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1106588

Other (OTH) AF: 0.00 AC: 0 AN: 59958

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Benign	0.043	D
Sift4G	Benign	0.064	T
Polyphen		1.0	D
Vest4		0.49
MutPred		0.29		Gain of disorder (P = 0.159)
MVP		0.068
MPC		1.3
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.23
gMVP		0.89
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs773509797; hg19: chr14-74823883;