rs28360135

Variant names:

• chr5-83195855-T-C
• rs28360135
• NM_003401.5:c.401T>C

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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
• Publications: 24 publications found

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]

XRCC4 Gene-Disease associations (from GenCC):

• short stature, microcephaly, and endocrine dysfunction

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003401.5. 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
	XRCC4	NM_003401.5	MANE Select	c.401T>C	p.Ile134Thr	missense	Exon 4 of 8	NP_003392.1
	XRCC4	NM_001318012.3		c.401T>C	p.Ile134Thr	missense	Exon 4 of 8	NP_001304941.1
	XRCC4	NM_022406.5		c.401T>C	p.Ile134Thr	missense	Exon 4 of 8	NP_071801.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.401T>C	p.Ile134Thr	missense	Exon 4 of 8	ENSP00000379344.4
	XRCC4	ENST00000511817.1	TSL:1	c.401T>C	p.Ile134Thr	missense	Exon 4 of 8	ENSP00000421491.1
	XRCC4	ENST00000282268.7	TSL:1	c.401T>C	p.Ile134Thr	missense	Exon 4 of 8	ENSP00000282268.3

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

GnomAD2 exomes AF: 0.0255 AC: 6400 AN: 250638 AF XY: 0.0266

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 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

African (AFR) AF: 0.00616 AC: 206 AN: 33440

American (AMR) AF: 0.0291 AC: 1300 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 504 AN: 26062

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39596

South Asian (SAS) AF: 0.0174 AC: 1493 AN: 85980

European-Finnish (FIN) AF: 0.0101 AC: 536 AN: 53298

Middle Eastern (MID) AF: 0.0292 AC: 168 AN: 5756

European-Non Finnish (NFE) AF: 0.0366 AC: 40634 AN: 1110686

Other (OTH) AF: 0.0309 AC: 1861 AN: 60286

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

African (AFR) AF: 0.00761 AC: 316 AN: 41540

American (AMR) AF: 0.0412 AC: 630 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3462

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4826

European-Finnish (FIN) AF: 0.0137 AC: 145 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0383 AC: 2604 AN: 67946

Other (OTH) AF: 0.0371 AC: 78 AN: 2104

Alfa AF: 0.0326 Hom.: 313

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.066
Sift	Benign	0.37	T
Sift4G	Benign	0.61	T
Polyphen		0.95	P
Vest4		0.10
MPC		0.21
ClinPred		0.017	T
GERP RS		5.6
Varity_R		0.16
gMVP		0.28
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28360135; hg19: chr5-82491674;