14-74357601-T-C

Variant names:

• chr14-74357601-T-C
• rs140227220
• NM_018228.3:c.818T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018228.3(VRTN):​c.818T>C​(p.Leu273Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: VRTN NM_018228.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21920747).

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.818T>C	p.Leu273Pro	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.818T>C	p.Leu273Pro	missense	Exon 2 of 2	ENSP00000256362.4	Q9H8Y1
	VRTN	ENST00000925859.1		c.818T>C	p.Leu273Pro	missense	Exon 2 of 2	ENSP00000595918.1
	VRTN	ENST00000925860.1		c.818T>C	p.Leu273Pro	missense	Exon 3 of 3	ENSP00000595919.1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000414 AC: 104 AN: 251110 AF XY: 0.000324

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000280 AC: 409 AN: 1461722 Hom.: 0 Cov.: 31 AF XY: 0.000253 AC XY: 184 AN XY: 727182

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00183 AC: 82 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000276 AC: 307 AN: 1112008

Other (OTH) AF: 0.000281 AC: 17 AN: 60394

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000632 AC XY: 47 AN XY: 74354

African (AFR) AF: 0.0000965 AC: 4 AN: 41468

American (AMR) AF: 0.00334 AC: 51 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68030

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000419 Hom.: 0

Bravo AF: 0.000699

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.071	B
Vest4		0.78
MVP		0.62
MPC		1.6
ClinPred		0.058	T
GERP RS		2.8
Varity_R		0.61
gMVP		0.76
Mutation Taster		=59/41	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: rs140227220; hg19: chr14-74824304;