3-39184094-C-T

Position:

• chr3-39184094-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_194293.4(XIRP1):​c.5352G>A​(p.Met1784Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00974 in 1,606,360 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.010 (98 hom.)
• Consequence: XIRP1 NM_194293.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.15

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00334993).
• BP6: Variant 3-39184094-C-T is Benign according to our data. Variant chr3-39184094-C-T is described in ClinVar as [Benign]. Clinvar id is 781707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-39184094-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XIRP1	NM_194293.4	c.5352G>A	p.Met1784Ile	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.5352G>A	p.Met1784Ile	missense_variant	2/2	1	NM_194293.4	ENSP00000343140	A2
XIRP1	ENST00000421646.1	c.1401G>A	p.Met467Ile	missense_variant	2/2	1		ENSP00000391645
XIRP1	ENST00000396251.1	c.*1559G>A		3_prime_UTR_variant	3/3	1		ENSP00000379550	P2

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1126 AN: 152216 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00766 AC: 1894 AN: 247268 Hom.: 11 AF XY: 0.00769 AC XY: 1026 AN XY: 133406

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00866

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000440

Gnomad FIN exome AF: 0.000702

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00999 AC: 14525 AN: 1454026 Hom.: 98 Cov.: 29 AF XY: 0.00971 AC XY: 7008 AN XY: 721900

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.00905

Gnomad4 ASJ exome AF: 0.0308

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000445

Gnomad4 FIN exome AF: 0.000620

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00739 AC: 1125 AN: 152334 Hom.: 8 Cov.: 32 AF XY: 0.00689 AC XY: 513 AN XY: 74476

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0106 Hom.: 14

Bravo AF: 0.00814

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0133 AC: 114

ExAC AF: 0.00709 AC: 861

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	XIRP1: BP4, BS1, BS2 -
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

Jun 12, 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	0.21
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.96
DANN	Benign	0.93
DEOGEN2	Benign	0.074	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.079
Sift	Benign	0.15	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0040	B;.
Vest4		0.11
MutPred		0.24		Loss of glycosylation at T1787 (P = 0.0239);.;
MVP		0.13
MPC		0.075
ClinPred		0.0095	T
GERP RS		-8.0
Varity_R		0.050
gMVP		0.083

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: rs146284335; hg19: chr3-39225585;