dbSNP rs1017794: XRCC4:c.-11+8621C>A (chr5-83086236-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is . The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003401.5(XRCC4):c.-11+8621C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 151,904 control chromosomes in the GnomAD database, including 19,584 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.50 ( 19584 hom., cov: 31)

Consequence

XRCC4
NM_003401.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.140

Publications

6 publications found

Variant links:

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, PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
microcephalic primordial dwarfism-insulin resistance syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

XRCC4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003401.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XRCC4	NM_003401.5	MANE Select	c.-11+8621C>A	intron	N/A	NP_003392.1	Q13426-2
XRCC4	NM_001318012.3		c.-11+8574C>A	intron	N/A	NP_001304941.1	Q13426-1
XRCC4	NM_022406.5		c.-11+8621C>A	intron	N/A	NP_071801.1	Q13426-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.-11+8621C>A	intron	N/A	ENSP00000379344.4	Q13426-2
XRCC4	ENST00000511817.1	TSL:1	c.-11+8574C>A	intron	N/A	ENSP00000421491.1	Q13426-1
XRCC4	ENST00000282268.7	TSL:1	c.-11+8574C>A	intron	N/A	ENSP00000282268.3	Q13426-2

Frequencies

GnomAD3 genomes

AF:

0.496

AC:

75220

AN:

151786

Hom.:

19560

Cov.:

show subpopulations

Gnomad AFR

AF:

0.648

Gnomad AMI

AF:

0.532

Gnomad AMR

AF:

0.348

Gnomad ASJ

AF:

0.389

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.516

Gnomad FIN

AF:

0.495

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.464

Gnomad OTH

AF:

0.461

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.496

AC:

75276

AN:

151904

Hom.:

19584

Cov.:

AF XY:

0.493

AC XY:

36612

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.648

AC:

26852

AN:

41420

American (AMR)

AF:

0.348

AC:

5306

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.389

AC:

1350

AN:

3468

East Asian (EAS)

AF:

0.193

AC:

994

AN:

5156

South Asian (SAS)

AF:

0.514

AC:

2479

AN:

4820

European-Finnish (FIN)

AF:

0.495

AC:

5217

AN:

10546

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.464

AC:

31507

AN:

67922

Other (OTH)

AF:

0.460

AC:

972

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1875

3750

5624

7499

9374

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.469

Hom.:

8921

Bravo

AF:

0.485

Asia WGS

AF:

0.369

AC:

1282

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.8

(source)

DANN

Benign

0.76

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

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.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over