chr5-83111013-T-C

Variant names:

• chr5-83111013-T-C
• rs375480555
• NM_003401.5:c.140-15T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_003401.5(XRCC4):​c.140-15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,596,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.39
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-83111013-T-C is Benign according to our data. Variant chr5-83111013-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1631696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.140-15T>C		intron	N/A	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.140-15T>C		intron	N/A	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.140-15T>C		intron	N/A	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.140-15T>C		intron	N/A	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.140-15T>C		intron	N/A	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.140-15T>C		intron	N/A	ENSP00000282268.3	Q13426-2

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000232 AC: 54 AN: 232642 AF XY: 0.000278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000375

Gnomad NFE exome AF: 0.000400

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000355 AC: 512 AN: 1444154 Hom.: 0 Cov.: 30 AF XY: 0.000341 AC XY: 245 AN XY: 718076

African (AFR) AF: 0.0000931 AC: 3 AN: 32234

American (AMR) AF: 0.000101 AC: 4 AN: 39684

Ashkenazi Jewish (ASJ) AF: 0.000312 AC: 8 AN: 25602

East Asian (EAS) AF: 0.00 AC: 0 AN: 39294

South Asian (SAS) AF: 0.000110 AC: 9 AN: 82116

European-Finnish (FIN) AF: 0.000320 AC: 17 AN: 53098

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5726

European-Non Finnish (NFE) AF: 0.000405 AC: 448 AN: 1106738

Other (OTH) AF: 0.000335 AC: 20 AN: 59662

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74448

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 67960

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.000230

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.5
DANN	Benign	0.55
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs375480555; hg19: chr5-82406832;