rs28383151

Variant names:

• chr5-83111054-G-A
• rs28383151
• NM_003401.5:c.166G>A
• XRCC4 p.Ala56Thr

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003401.5(XRCC4):​c.166G>A​(p.Ala56Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000786 in 1,608,256 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (3 hom.)
• Consequence: XRCC4 NM_003401.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.49
• Publications: 14 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), Laboratory for Molecular Medicine, G2P
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 3 AR,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	NM_003401.5	MANE Select	c.166G>A	p.Ala56Thr	missense	Exon 3 of 8	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.166G>A	p.Ala56Thr	missense	Exon 3 of 8	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.166G>A	p.Ala56Thr	missense	Exon 3 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.166G>A	p.Ala56Thr	missense	Exon 3 of 8	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.166G>A	p.Ala56Thr	missense	Exon 3 of 8	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.166G>A	p.Ala56Thr	missense	Exon 3 of 8	ENSP00000282268.3	Q13426-2

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152052 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000839

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000429 AC: 105 AN: 244886 AF XY: 0.000400

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000758

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000681

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000812 AC: 1183 AN: 1456086 Hom.: 3 Cov.: 30 AF XY: 0.000787 AC XY: 570 AN XY: 724190

African (AFR) AF: 0.000181 AC: 6 AN: 33132

American (AMR) AF: 0.000896 AC: 39 AN: 43530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 84602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000985 AC: 1093 AN: 1110182

Other (OTH) AF: 0.000748 AC: 45 AN: 60162

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74414

African (AFR) AF: 0.000241 AC: 10 AN: 41546

American (AMR) AF: 0.000720 AC: 11 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000839 AC: 57 AN: 67922

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.000385 Hom.: 1

Bravo AF: 0.000691

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Short stature, microcephaly, and endocrine dysfunction (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.40
Mutation Taster		=45/55	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28383151;

hg19: chr5-82406873;