22-43999571-T-C

Variant names:

• chr22-43999571-T-C
• rs1007863
• ENST00000406477.7:c.109T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000406477.7(PARVB):​c.109T>C​(p.Trp37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,611,162 control chromosomes in the GnomAD database, including 141,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.48 (17972 hom., cov: 32)
  • Exomes 𝑓: 0.41 (123132 hom.)
• Consequence: PARVB ENST00000406477.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.50
• Publications: 38 publications found

Genes affected

PARVB (HGNC:14653): (parvin beta) This gene encodes a member of the parvin family of actin-binding proteins, which play a role in cytoskeleton organization and cell adhesion. These proteins are associated with focal contacts and contain calponin homology domains that bind to actin filaments. This family member binds to alphaPIX and alpha-actinin, and it can inhibit the activity of integrin-linked kinase. This protein also functions in tumor suppression. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

SAMM50 (HGNC:24276): (SAMM50 sorting and assembly machinery component) This gene encodes a component of the Sorting and Assembly Machinery (SAM) of the mitochondrial outer membrane. The Sam complex functions in the assembly of beta-barrel proteins into the outer mitochondrial membrane.[provided by RefSeq, Jun 2011]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.1052323E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000406477.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARVB	NM_001003828.3		c.109T>C	p.Trp37Arg	missense	Exon 2 of 14	NP_001003828.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARVB	ENST00000406477.7	TSL:1	c.109T>C	p.Trp37Arg	missense	Exon 2 of 14	ENSP00000384515.3
	SAMM50	ENST00000465768.1	TSL:3	n.79+9165T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72283 AN: 151838 Hom.: 17964 Cov.: 32

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.461

GnomAD2 exomes AF: 0.440 AC: 108874 AN: 247280 AF XY: 0.437

Gnomad AFR exome AF: 0.634

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.488

Gnomad FIN exome AF: 0.470

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.437

GnomAD4 exome AF: 0.407 AC: 594319 AN: 1459206 Hom.: 123132 Cov.: 32 AF XY: 0.409 AC XY: 296843 AN XY: 726078

African (AFR) AF: 0.628 AC: 21009 AN: 33446

American (AMR) AF: 0.440 AC: 19693 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 9305 AN: 26116

East Asian (EAS) AF: 0.495 AC: 19638 AN: 39690

South Asian (SAS) AF: 0.469 AC: 40415 AN: 86194

European-Finnish (FIN) AF: 0.469 AC: 25028 AN: 53398

Middle Eastern (MID) AF: 0.446 AC: 2567 AN: 5760

European-Non Finnish (NFE) AF: 0.389 AC: 431668 AN: 1109608

Other (OTH) AF: 0.415 AC: 24996 AN: 60272

GnomAD4 genome AF: 0.476 AC: 72318 AN: 151956 Hom.: 17972 Cov.: 32 AF XY: 0.479 AC XY: 35602 AN XY: 74276

African (AFR) AF: 0.624 AC: 25874 AN: 41448

American (AMR) AF: 0.465 AC: 7091 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1234 AN: 3472

East Asian (EAS) AF: 0.490 AC: 2523 AN: 5154

South Asian (SAS) AF: 0.475 AC: 2283 AN: 4806

European-Finnish (FIN) AF: 0.471 AC: 4970 AN: 10556

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26715 AN: 67964

Other (OTH) AF: 0.456 AC: 962 AN: 2108

Alfa AF: 0.431 Hom.: 37051

Bravo AF: 0.483

TwinsUK AF: 0.395 AC: 1465

ALSPAC AF: 0.397 AC: 1531

ESP6500AA AF: 0.584 AC: 2375

ESP6500EA AF: 0.380 AC: 3171

ExAC AF: 0.443 AC: 53523

Asia WGS AF: 0.484 AC: 1681 AN: 3478

EpiCase AF: 0.404

EpiControl AF: 0.407

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.042
DANN	Benign	0.27
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.00062	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0000071	T
MetaSVM	Benign	-0.95	T
PhyloP100		-2.5
PROVEAN	Benign	0.68	N
REVEL	Benign	0.0050
Sift	Benign	0.97	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0070	B
Vest4		0.012
MutPred		0.38		Gain of methylation at W37 (P = 0.0153)
MPC		0.29
ClinPred		0.0085	T
GERP RS		-3.8
PromoterAI		0.015	Neutral
gMVP		0.052
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1007863; hg19: chr22-44395451; COSMIC: COSV63109519; COSMIC: COSV63109519;