chr5-83195855-T-C

Position:

• chr5-83195855-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003401.5(XRCC4):​c.401T>C​(p.Ile134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,611,916 control chromosomes in the GnomAD database, including 950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.026 (78 hom., cov: 32)
  • Exomes 𝑓: 0.032 (872 hom.)
• Consequence: XRCC4 NM_003401.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.70

Genes affected

XRCC4 (HGNC:12831): (X-ray repair cross complementing 4) The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037754476).
• BP6: Variant 5-83195855-T-C is Benign according to our data. Variant chr5-83195855-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1300523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0261 (3969/152142) while in subpopulation AMR AF= 0.0412 (630/15274). AF 95% confidence interval is 0.0386. There are 78 homozygotes in gnomad4. There are 1860 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 78 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC4	NM_003401.5	c.401T>C	p.Ile134Thr	missense_variant	4/8	ENST00000396027.9	NP_003392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC4	ENST00000396027.9	c.401T>C	p.Ile134Thr	missense_variant	4/8	5	NM_003401.5	ENSP00000379344	A1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3973 AN: 152024 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00763

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0414

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0383

Gnomad OTH AF: 0.0375

GnomAD3 exomes AF: 0.0255 AC: 6400 AN: 250638 Hom.: 108 AF XY: 0.0266 AC XY: 3607 AN XY: 135590

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.0287

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0155

Gnomad FIN exome AF: 0.00981

Gnomad NFE exome AF: 0.0371

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0320 AC: 46707 AN: 1459774 Hom.: 872 Cov.: 30 AF XY: 0.0320 AC XY: 23228 AN XY: 726168

Gnomad4 AFR exome AF: 0.00616

Gnomad4 AMR exome AF: 0.0291

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0174

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.0366

Gnomad4 OTH exome AF: 0.0309

GnomAD4 genome AF: 0.0261 AC: 3969 AN: 152142 Hom.: 78 Cov.: 32 AF XY: 0.0250 AC XY: 1860 AN XY: 74384

Gnomad4 AFR AF: 0.00761

Gnomad4 AMR AF: 0.0412

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0147

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0383

Gnomad4 OTH AF: 0.0371

Alfa AF: 0.0336 Hom.: 159

Bravo AF: 0.0267

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0413 AC: 159

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.0406 AC: 349

ExAC AF: 0.0249 AC: 3029

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 22466227, 16741161, 26764160) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	.;T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T;.;.;T
MetaRNN	Benign	0.0038	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L;L
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.37	T;T;T;T
Sift4G	Benign	0.61	T;T;T;T
Polyphen		0.95	P;D;P;D
Vest4		0.10
MPC		0.21
ClinPred		0.017	T
GERP RS		5.6
Varity_R		0.16
gMVP		0.28

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: rs28360135; hg19: chr5-82491674;