chr11-12473959-C-A

Variant names:

• chr11-12473959-C-A
• rs1398743718
• NM_018222.5:c.273C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018222.5(PARVA):​c.273C>A​(p.Asp91Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,428,902 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D91V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PARVA NM_018222.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.816
• Publications: 0 publications found

Genes affected

PARVA (HGNC:14652): (parvin alpha) This gene encodes a member of the parvin family of actin-binding proteins. Parvins are associated with focal contacts and contain calponin homology domains that bind to actin filaments. The encoded protein is part of the integrin-linked kinase signaling complex and plays a role in cell adhesion, motility and survival. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2938913).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018222.5. 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
	PARVA	NM_018222.5	MANE Select	c.273C>A	p.Asp91Glu	missense	Exon 3 of 13	NP_060692.3	Q9NVD7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARVA	ENST00000334956.15	TSL:1 MANE Select	c.273C>A	p.Asp91Glu	missense	Exon 3 of 13	ENSP00000334008.9	Q9NVD7-1
	PARVA	ENST00000903583.1		c.273C>A	p.Asp91Glu	missense	Exon 3 of 14	ENSP00000573642.1
	PARVA	ENST00000903580.1		c.273C>A	p.Asp91Glu	missense	Exon 3 of 13	ENSP00000573639.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000101 AC: 2 AN: 197840 AF XY: 0.00000949

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1428902 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 707418

African (AFR) AF: 0.00 AC: 0 AN: 32764

American (AMR) AF: 0.00 AC: 0 AN: 39676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25472

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37958

South Asian (SAS) AF: 0.00 AC: 0 AN: 81040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095576

Other (OTH) AF: 0.00 AC: 0 AN: 59282

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.20
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.82
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.16
Sift	Benign	0.051	T
Sift4G	Benign	0.11	T
Polyphen		0.076	B
MutPred		0.20		Gain of methylation at K93 (P = 0.0774)
MVP		0.15
MPC		0.62
ClinPred		0.79	D
GERP RS		5.2
Varity_R		0.30
gMVP		0.44
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1398743718; hg19: chr11-12495506;