chr17-35100946-G-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000586044.5(RAD51D):​n.*725C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,608,262 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RAD51D
ENST00000586044.5 non_coding_transcript_exon

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.333

Publications

0 publications found
Variant links:
Genes affected
RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]
RAD51D Gene-Disease associations (from GenCC):
  • breast-ovarian cancer, familial, susceptibility to, 4
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • hereditary breast ovarian cancer syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary breast carcinoma
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 17-35100946-G-A is Benign according to our data. Variant chr17-35100946-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 378464. Variant chr17-35100946-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 378464. Variant chr17-35100946-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 378464.
BS2
High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAD51DNM_002878.4 linkc.*7C>T 3_prime_UTR_variant Exon 10 of 10 ENST00000345365.11 NP_002869.3 O75771-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAD51DENST00000345365.11 linkc.*7C>T 3_prime_UTR_variant Exon 10 of 10 1 NM_002878.4 ENSP00000338790.6 O75771-1
ENSG00000267618ENST00000593039.5 linkc.426+255C>T intron_variant Intron 5 of 6 2 ENSP00000466834.1 K7EN88

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000437
AC:
11
AN:
251484
AF XY:
0.0000294
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000206
AC:
30
AN:
1456080
Hom.:
0
Cov.:
30
AF XY:
0.0000152
AC XY:
11
AN XY:
724830
show subpopulations
African (AFR)
AF:
0.000811
AC:
27
AN:
33294
American (AMR)
AF:
0.0000447
AC:
2
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26100
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86112
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5694
European-Non Finnish (NFE)
AF:
9.03e-7
AC:
1
AN:
1106870
Other (OTH)
AF:
0.00
AC:
0
AN:
60196
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74340
show subpopulations
African (AFR)
AF:
0.000531
AC:
22
AN:
41442
American (AMR)
AF:
0.000131
AC:
2
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.515
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000772
Hom.:
0
Bravo
AF:
0.000215

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Nov 30, 2021
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 20, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Uncertain:1
Sep 14, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00052 (13/24964 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect RAD51D mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Benign:1
Nov 08, 2016
Color Diagnostics, LLC DBA Color Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
3.1
DANN
Benign
0.59
PhyloP100
0.33
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs370985675; hg19: chr17-33427965; API