rs1746131507

Variant names:

• chr5-83105049-A-T
• rs1746131507
• NM_003401.5:c.130A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003401.5(XRCC4):​c.130A>T​(p.Thr44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T44T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: XRCC4 NM_003401.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

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

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18727514).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.130A>T	p.Thr44Ser	missense	Exon 2 of 8	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.130A>T	p.Thr44Ser	missense	Exon 2 of 8	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.130A>T	p.Thr44Ser	missense	Exon 2 of 8	NP_071801.1	Q13426-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.130A>T	p.Thr44Ser	missense	Exon 2 of 8	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.130A>T	p.Thr44Ser	missense	Exon 2 of 8	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.130A>T	p.Thr44Ser	missense	Exon 2 of 8	ENSP00000282268.3	Q13426-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459254 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725878

African (AFR) AF: 0.00 AC: 0 AN: 33262

American (AMR) AF: 0.00 AC: 0 AN: 44258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111150

Other (OTH) AF: 0.00 AC: 0 AN: 60246

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Short stature, microcephaly, and endocrine dysfunction (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.047
Sift	Benign	0.43	T
Sift4G	Benign	0.62	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.66		Gain of glycosylation at T44 (P = 0.0197)
MVP		0.46
MPC		0.16
ClinPred		0.62	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.22
Mutation Taster		=66/34	polymorphism

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: rs1746131507; hg19: chr5-82400868;