19-5908961-G-C

Variant names:

• chr19-5908961-G-C
• rs373959013
• NM_001017921.4:c.329G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017921.4(VMAC):​c.329G>C​(p.Arg110Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. R110H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VMAC NM_001017921.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098284215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMAC	NM_001017921.4	c.329G>C	p.Arg110Pro	missense_variant	Exon 2 of 2	ENST00000339485.4	NP_001017921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VMAC	ENST00000339485.4	c.329G>C	p.Arg110Pro	missense_variant	Exon 2 of 2	1	NM_001017921.4	ENSP00000343348.2
ENSG00000267314	ENST00000588891.1	n.191+3880G>C		intron_variant	Intron 1 of 3	4		ENSP00000468419.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460498 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726592

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111588

Other (OTH) AF: 0.00 AC: 0 AN: 60330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.54
DANN	Benign	0.65
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.056
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.095
Sift	Benign	0.20	T
Sift4G	Benign	0.091	T
Polyphen		0.25	B
Vest4		0.26
MutPred		0.21		Gain of helix (P = 0.062);
MVP		0.040
MPC		0.84
ClinPred		0.17	T
GERP RS		-3.2
Varity_R		0.29
gMVP		0.56
Mutation Taster		=97/3	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: rs373959013; hg19: chr19-5908972;