3-39184325-C-A

Position:

• chr3-39184325-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194293.4(XIRP1):​c.5121G>T​(p.Gln1707His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,614,218 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.017 (84 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (83 hom.)
• Consequence: XIRP1 NM_194293.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.746

Genes affected

XIRP1 (HGNC:14301): (xin actin binding repeat containing 1) The protein encoded by this gene is a striated muscle protein and belongs to the Xin actin-binding repeat-containing protein (XIRP) family. The protein functions to protect actin filaments during depolymerization. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002465427).
• BP6: Variant 3-39184325-C-A is Benign according to our data. Variant chr3-39184325-C-A is described in ClinVar as [Benign]. Clinvar id is 786008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XIRP1	NM_194293.4	c.5121G>T	p.Gln1707His	missense_variant	2/2	ENST00000340369.4	NP_919269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XIRP1	ENST00000340369.4	c.5121G>T	p.Gln1707His	missense_variant	2/2	1	NM_194293.4	ENSP00000343140	A2
XIRP1	ENST00000421646.1	c.1170G>T	p.Gln390His	missense_variant	2/2	1		ENSP00000391645
XIRP1	ENST00000396251.1	c.*1328G>T		3_prime_UTR_variant	3/3	1		ENSP00000379550	P2

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2574 AN: 152214 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00434 AC: 1092 AN: 251458 Hom.: 36 AF XY: 0.00322 AC XY: 438 AN XY: 135904

Gnomad AFR exome AF: 0.0572

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00190 AC: 2783 AN: 1461886 Hom.: 83 Cov.: 29 AF XY: 0.00167 AC XY: 1213 AN XY: 727242

Gnomad4 AFR exome AF: 0.0611

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.0169 AC: 2582 AN: 152332 Hom.: 84 Cov.: 33 AF XY: 0.0164 AC XY: 1222 AN XY: 74500

Gnomad4 AFR AF: 0.0585

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00306 Hom.: 15

Bravo AF: 0.0190

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0597 AC: 263

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00529 AC: 642

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

XIRP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.031
Sift	Benign	0.20	T;T
Sift4G	Benign	0.11	T;D
Polyphen		0.0030	B;.
Vest4		0.23
MutPred		0.11		Gain of helix (P = 0.0093);.;
MVP		0.067
MPC		0.25
ClinPred		0.024	T
GERP RS		0.26
Varity_R		0.048
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs34053674; hg19: chr3-39225816; COSMIC: COSV99080151;