Variant 5-34908937-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002853.4(RAD1):c.677C>T(p.Ser226Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RAD1
NM_002853.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.44

Variant links:

Genes affected

RAD1 (HGNC:9806): (RAD1 checkpoint DNA exonuclease) This gene encodes a component of a heterotrimeric cell cycle checkpoint complex, known as the 9-1-1 complex, that is activated to stop cell cycle progression in response to DNA damage or incomplete DNA replication. The 9-1-1 complex is recruited by RAD17 to affected sites where it may attract specialized DNA polymerases and other DNA repair effectors. Alternatively spliced transcript variants of this gene have been described. [provided by RefSeq, Jan 2009]

RAD1 links:

TTC23L (HGNC:):

TTC23L links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RAD1	NM_002853.4 linkuse as main transcript	c.677C>T	p.Ser226Phe	missense_variant	6/6	ENST00000382038.7	NP_002844.1
RAD1	NR_026591.2 linkuse as main transcript	n.726C>T		non_coding_transcript_exon_variant	5/5
TTC23L	NR_169875.1 linkuse as main transcript	n.974-9427G>A		intron_variant, non_coding_transcript_variant
TTC23L	NR_169876.1 linkuse as main transcript	n.1048-9427G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD1	ENST00000382038.7 linkuse as main transcript	c.677C>T	p.Ser226Phe	missense_variant	6/6	1	NM_002853.4	ENSP00000371469	P1	O60671-1
RAD1	ENST00000325577.8 linkuse as main transcript	c.*361C>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	1		ENSP00000313467		O60671-3
RAD1	ENST00000341754.8 linkuse as main transcript	c.677C>T	p.Ser226Phe	missense_variant	9/9	5		ENSP00000340879	P1	O60671-1
RAD1	ENST00000513914.5 linkuse as main transcript	c.*522C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	5		ENSP00000421007

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453916

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723288

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.677C>T (p.S226F) alteration is located in exon 6 (coding exon 5) of the RAD1 gene. This alteration results from a C to T substitution at nucleotide position 677, causing the serine (S) at amino acid position 226 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D

M_CAP

Benign

0.046

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.88

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.97

D;D

Vest4

0.69

MutPred

0.63

Loss of disorder (P = 0.0957);Loss of disorder (P = 0.0957);

MVP

0.56

MPC

0.29

ClinPred

0.98

GERP RS

5.7

Varity_R

0.59

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over