chr19-5904904-C-G

Variant names:

• chr19-5904904-C-G
• rs374909914
• NM_001017921.4:c.14C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001017921.4(VMAC):​c.14C>G​(p.Pro5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,482,952 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000059 (2 hom.)
• Consequence: VMAC NM_001017921.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• Publications: 0 publications found

Genes affected

VMAC (HGNC:33803): (vimentin type intermediate filament associated coiled-coil protein) Predicted to be located in cytoplasm. Predicted to be active in type III intermediate filament. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267314 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0436441).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMAC	NM_001017921.4	c.14C>G	p.Pro5Arg	missense_variant	Exon 1 of 2	ENST00000339485.4	NP_001017921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VMAC	ENST00000339485.4	c.14C>G	p.Pro5Arg	missense_variant	Exon 1 of 2	1	NM_001017921.4	ENSP00000343348.2
ENSG00000267314	ENST00000588891.1	n.14C>G		non_coding_transcript_exon_variant	Exon 1 of 4	4		ENSP00000468419.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000122 AC: 10 AN: 81904 AF XY: 0.000105

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000448

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000946

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000586 AC: 78 AN: 1330754 Hom.: 2 Cov.: 31 AF XY: 0.0000548 AC XY: 36 AN XY: 656988

African (AFR) AF: 0.00 AC: 0 AN: 26756

American (AMR) AF: 0.000259 AC: 7 AN: 27008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23164

East Asian (EAS) AF: 0.0000341 AC: 1 AN: 29336

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73452

European-Finnish (FIN) AF: 0.0000607 AC: 2 AN: 32962

Middle Eastern (MID) AF: 0.000256 AC: 1 AN: 3900

European-Non Finnish (NFE) AF: 0.0000604 AC: 64 AN: 1058956

Other (OTH) AF: 0.0000362 AC: 2 AN: 55220

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000214 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14C>G (p.P5R) alteration is located in exon 1 (coding exon 1) of the VMAC gene. This alteration results from a C to G substitution at nucleotide position 14, causing the proline (P) at amino acid position 5 to be replaced by an arginine (R). 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	0.19
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.026
Sift	Benign	0.096	T
Sift4G	Benign	0.088	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.31		Gain of MoRF binding (P = 0);
MVP		0.040
MPC		0.90
ClinPred		0.086	T
GERP RS		1.0
PromoterAI		0.086	Neutral
Varity_R		0.035
gMVP		0.15
Mutation Taster		=99/1	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: rs374909914; hg19: chr19-5904915;