NM_003401.5:c.894-7G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_003401.5(XRCC4):​c.894-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,588,702 control chromosomes in the GnomAD database, including 33,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 7046 hom., cov: 32)
Exomes 𝑓: 0.15 ( 26237 hom. )

Consequence

XRCC4
NM_003401.5 splice_region, intron

Scores

7
Splicing: ADA: 0.9953
1
1

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.825
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant 5-83353124-G-A is Benign according to our data. Variant chr5-83353124-G-A is described in ClinVar as [Benign]. Clinvar id is 1237727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XRCC4NM_003401.5 linkc.894-7G>A splice_region_variant, intron_variant Intron 7 of 7 ENST00000396027.9 NP_003392.1 Q13426-2A0A024RAL0Q7Z763

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XRCC4ENST00000396027.9 linkc.894-7G>A splice_region_variant, intron_variant Intron 7 of 7 5 NM_003401.5 ENSP00000379344.4 Q13426-2
XRCC4ENST00000511817.1 linkc.894-1G>A splice_acceptor_variant, intron_variant Intron 7 of 7 1 ENSP00000421491.1 Q13426-1
XRCC4ENST00000282268.7 linkc.894-7G>A splice_region_variant, intron_variant Intron 7 of 7 1 ENSP00000282268.3 Q13426-2
XRCC4ENST00000338635.10 linkc.894-1G>A splice_acceptor_variant, intron_variant Intron 7 of 7 2 ENSP00000342011.6 Q13426-1

Frequencies

GnomAD3 genomes
AF:
0.254
AC:
38515
AN:
151706
Hom.:
7017
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.446
Gnomad AMI
AF:
0.0559
Gnomad AMR
AF:
0.314
Gnomad ASJ
AF:
0.151
Gnomad EAS
AF:
0.710
Gnomad SAS
AF:
0.174
Gnomad FIN
AF:
0.186
Gnomad MID
AF:
0.209
Gnomad NFE
AF:
0.113
Gnomad OTH
AF:
0.238
GnomAD3 exomes
AF:
0.226
AC:
52222
AN:
231376
Hom.:
9749
AF XY:
0.208
AC XY:
26176
AN XY:
125682
show subpopulations
Gnomad AFR exome
AF:
0.449
Gnomad AMR exome
AF:
0.381
Gnomad ASJ exome
AF:
0.139
Gnomad EAS exome
AF:
0.717
Gnomad SAS exome
AF:
0.152
Gnomad FIN exome
AF:
0.185
Gnomad NFE exome
AF:
0.113
Gnomad OTH exome
AF:
0.186
GnomAD4 exome
AF:
0.149
AC:
214456
AN:
1436878
Hom.:
26237
Cov.:
29
AF XY:
0.148
AC XY:
105541
AN XY:
714916
show subpopulations
Gnomad4 AFR exome
AF:
0.454
Gnomad4 AMR exome
AF:
0.368
Gnomad4 ASJ exome
AF:
0.144
Gnomad4 EAS exome
AF:
0.700
Gnomad4 SAS exome
AF:
0.157
Gnomad4 FIN exome
AF:
0.185
Gnomad4 NFE exome
AF:
0.109
Gnomad4 OTH exome
AF:
0.183
GnomAD4 genome
AF:
0.254
AC:
38587
AN:
151824
Hom.:
7046
Cov.:
32
AF XY:
0.260
AC XY:
19250
AN XY:
74174
show subpopulations
Gnomad4 AFR
AF:
0.447
Gnomad4 AMR
AF:
0.314
Gnomad4 ASJ
AF:
0.151
Gnomad4 EAS
AF:
0.710
Gnomad4 SAS
AF:
0.172
Gnomad4 FIN
AF:
0.186
Gnomad4 NFE
AF:
0.113
Gnomad4 OTH
AF:
0.242
Alfa
AF:
0.150
Hom.:
7056
Bravo
AF:
0.278
TwinsUK
AF:
0.109
AC:
406
ALSPAC
AF:
0.106
AC:
410
ESP6500AA
AF:
0.439
AC:
1933
ESP6500EA
AF:
0.122
AC:
1052
ExAC
AF:
0.229
AC:
27740
Asia WGS
AF:
0.410
AC:
1422
AN:
3476

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 03, 2025- -
Benign, criteria provided, single submitterclinical testingGeneDxNov 13, 2018This variant is associated with the following publications: (PMID: 23663450, 17557904, 19408343) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.84
T
BayesDel_noAF
Benign
-0.84
CADD
Benign
14
DANN
Benign
0.46
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.00061
N
GERP RS
-0.065

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Benign
0.43
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.77
Position offset: 7
DS_AL_spliceai
0.99
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1805377; hg19: chr5-82648943; COSMIC: COSV56535232; API