dbSNP rs2075015: MDC1:p.Glu371Lys (chr6-30712831-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014641.3(MDC1):c.1111G>A(p.Glu371Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,613,004 control chromosomes in the GnomAD database, including 1,276 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.049 ( 359 hom., cov: 32)

Exomes 𝑓: 0.021 ( 917 hom. )

Consequence

MDC1
NM_014641.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.127

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013479888).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDC1	NM_014641.3 link	c.1111G>A	p.Glu371Lys	missense_variant	Exon 5 of 15	ENST00000376406.8	NP_055456.2	Q14676-1A0A1U9XBC1A1Z5I9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDC1	ENST00000376406.8 link	c.1111G>A	p.Glu371Lys	missense_variant	Exon 5 of 15	5	NM_014641.3	ENSP00000365588.3		Q14676-1
MDC1-AS1	ENST00000442150.1 link	n.385C>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0485

AC:

7384

AN:

152184

Hom.:

359

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0467

Gnomad ASJ

AF:

0.0591

Gnomad EAS

AF:

0.0617

Gnomad SAS

AF:

0.0249

Gnomad FIN

AF:

0.00687

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0593

GnomAD3 exomes

AF:

0.0312

AC:

7685

AN:

246230

Hom.:

238

AF XY:

0.0304

AC XY:

4081

AN XY:

134272

show subpopulations

Gnomad AFR exome

AF:

0.120

Gnomad AMR exome

AF:

0.0328

Gnomad ASJ exome

AF:

0.0675

Gnomad EAS exome

AF:

0.0534

Gnomad SAS exome

AF:

0.0302

Gnomad FIN exome

AF:

0.00634

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0351

GnomAD4 exome

AF:

0.0211

AC:

30748

AN:

1460702

Hom.:

917

Cov.:

AF XY:

0.0212

AC XY:

15390

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.125

Gnomad4 AMR exome

AF:

0.0355

Gnomad4 ASJ exome

AF:

0.0654

Gnomad4 EAS exome

AF:

0.111

Gnomad4 SAS exome

AF:

0.0297

Gnomad4 FIN exome

AF:

0.00685

Gnomad4 NFE exome

AF:

0.0125

Gnomad4 OTH exome

AF:

0.0292

GnomAD4 genome

AF:

0.0485

AC:

7391

AN:

152302

Hom.:

359

Cov.:

AF XY:

0.0480

AC XY:

3575

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.116

Gnomad4 AMR

AF:

0.0467

Gnomad4 ASJ

AF:

0.0591

Gnomad4 EAS

AF:

0.0619

Gnomad4 SAS

AF:

0.0245

Gnomad4 FIN

AF:

0.00687

Gnomad4 NFE

AF:

0.0143

Gnomad4 OTH

AF:

0.0582

Alfa

AF:

0.0277

Hom.:

235

Bravo

AF:

0.0563

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.108

AC:

325

ESP6500EA

AF:

0.0168

AC:

ExAC

AF:

0.0320

AC:

3761

Asia WGS

AF:

0.0420

AC:

145

AN:

3478

EpiCase

AF:

0.0227

EpiControl

AF:

0.0216

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.039

MetaRNN

Benign

0.0013

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.2

REVEL

Benign

0.056

Sift

Uncertain

0.0060

Sift4G

Benign

0.064

Polyphen

0.82

Vest4

0.10

MPC

0.80

ClinPred

0.014

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.042

gMVP

0.084

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over