6-30702873-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014641.3(MDC1):c.5870G>A(p.Arg1957His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,460,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MDC1
NM_014641.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.290

Publications

1 publications found

Variant links:

Genes affected

MDC1 (HGNC:21163): (mediator of DNA damage checkpoint 1) The protein encoded by this gene contains an N-terminal forkhead domain, two BRCA1 C-terminal (BRCT) motifs and a central domain with 13 repetitions of an approximately 41-amino acid sequence. The encoded protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage. This nuclear protein interacts with phosphorylated histone H2AX near sites of DNA double-strand breaks through its BRCT motifs, and facilitates recruitment of the ATM kinase and meiotic recombination 11 protein complex to DNA damage foci. [provided by RefSeq, Jul 2008]

MDC1 links:

MDC1-AS1 (HGNC:39764): (MDC1 antisense RNA 1)

MDC1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18959495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDC1	NM_014641.3 link	c.5870G>A	p.Arg1957His	missense_variant	Exon 13 of 15	ENST00000376406.8	NP_055456.2	Q14676-1A0A1U9XBC1A1Z5I9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MDC1	ENST00000376406.8 link	c.5870G>A	p.Arg1957His	missense_variant	Exon 13 of 15	5	NM_014641.3	ENSP00000365588.3	Q14676-1
MDC1	ENST00000489540.1 link	n.852G>A		non_coding_transcript_exon_variant	Exon 3 of 5	2
MDC1-AS1	ENST00000442150.1 link	n.-194C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000203

AC:

AN:

246504

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1460728

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726684

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1112008

Other (OTH)

AF:

0.0000331

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

ExAC

AF:

0.00000844

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 15, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5870G>A (p.R1957H) alteration is located in exon 13 (coding exon 12) of the MDC1 gene. This alteration results from a G to A substitution at nucleotide position 5870, causing the arginine (R) at amino acid position 1957 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.095

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.50

M_CAP

Benign

0.018

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.49

PhyloP100

0.29

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.2

REVEL

Benign

0.15

Sift

Benign

0.15

Sift4G

Benign

0.17

Polyphen

0.53

Vest4

0.25

MutPred

0.46

Loss of loop (P = 0.0512);

MVP

0.73

MPC

0.25

ClinPred

0.072

GERP RS

0.62

Varity_R

0.11

gMVP

0.33

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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6-30702873-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over