19-5905003-A-G

Variant names:

• chr19-5905003-A-G
• rs866543808
• NM_001017921.4:c.113A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001017921.4(VMAC):​c.113A>G​(p.His38Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000652 in 1,441,000 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: VMAC NM_001017921.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.98
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030105948).
• BP6: Variant 19-5905003-A-G is Benign according to our data. Variant chr19-5905003-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2344598.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VMAC	NM_001017921.4	c.113A>G	p.His38Arg	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.113A>G	p.His38Arg	missense_variant	Exon 1 of 2	1	NM_001017921.4	ENSP00000343348.2
ENSG00000267314	ENST00000588891.1	n.113A>G		non_coding_transcript_exon_variant	Exon 1 of 4	4		ENSP00000468419.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000663 AC: 3 AN: 45270 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000621 AC: 80 AN: 1288694 Hom.: 1 Cov.: 31 AF XY: 0.0000742 AC XY: 47 AN XY: 633478

African (AFR) AF: 0.000197 AC: 5 AN: 25356

American (AMR) AF: 0.000162 AC: 3 AN: 18474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21120

East Asian (EAS) AF: 0.00 AC: 0 AN: 28356

South Asian (SAS) AF: 0.0000601 AC: 4 AN: 66544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31976

Middle Eastern (MID) AF: 0.00389 AC: 15 AN: 3856

European-Non Finnish (NFE) AF: 0.0000442 AC: 46 AN: 1039646

Other (OTH) AF: 0.000131 AC: 7 AN: 53366

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152306 Hom.: 1 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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

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

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 03, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.71
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.1	N
PhyloP100		2.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.060
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.087
MVP		0.014
MPC		0.57
ClinPred		0.014	T
GERP RS		3.5
PromoterAI		-0.022	Neutral
Varity_R		0.039
gMVP		0.091
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs866543808; hg19: chr19-5905014;