Genetic Variant NM_014641.3:c.1157C>T (chr6-30712785-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014641.3(MDC1):c.1157C>T(p.Pro386Leu) 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 1,612,896 control chromosomes in the GnomAD database, including 1,278 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.049 ( 361 hom., cov: 32)

Exomes 𝑓: 0.021 ( 917 hom. )

Consequence

MDC1
NM_014641.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.810

Publications

10 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015835464).

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.1157C>T	p.Pro386Leu	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.1157C>T	p.Pro386Leu	missense_variant	Exon 5 of 15	5	NM_014641.3	ENSP00000365588.3		Q14676-1
MDC1-AS1	ENST00000442150.1 link	n.339G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0486

AC:

7388

AN:

152130

Hom.:

361

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0467

Gnomad ASJ

AF:

0.0591

Gnomad EAS

AF:

0.0618

Gnomad SAS

AF:

0.0248

Gnomad FIN

AF:

0.00687

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0594

GnomAD2 exomes

AF:

0.0312

AC:

7695

AN:

246460

AF XY:

0.0304

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 FIN exome

AF:

0.00643

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0351

GnomAD4 exome

AF:

0.0211

AC:

30748

AN:

1460648

Hom.:

917

Cov.:

AF XY:

0.0212

AC XY:

15391

AN XY:

726626

show subpopulations

African (AFR)

AF:

0.125

AC:

4191

AN:

33480

American (AMR)

AF:

0.0355

AC:

1587

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0654

AC:

1710

AN:

26136

East Asian (EAS)

AF:

0.111

AC:

4406

AN:

39698

South Asian (SAS)

AF:

0.0297

AC:

2559

AN:

86254

European-Finnish (FIN)

AF:

0.00689

AC:

360

AN:

52270

Middle Eastern (MID)

AF:

0.0560

AC:

323

AN:

5768

European-Non Finnish (NFE)

AF:

0.0125

AC:

13849

AN:

1111938

Other (OTH)

AF:

0.0292

AC:

1763

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1915

3829

5744

7658

9573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.0486

AC:

7395

AN:

152248

Hom.:

361

Cov.:

AF XY:

0.0480

AC XY:

3576

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.116

AC:

4835

AN:

41528

American (AMR)

AF:

0.0467

AC:

714

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0591

AC:

205

AN:

3468

East Asian (EAS)

AF:

0.0619

AC:

321

AN:

5184

South Asian (SAS)

AF:

0.0245

AC:

118

AN:

4826

European-Finnish (FIN)

AF:

0.00687

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0143

AC:

975

AN:

68014

Other (OTH)

AF:

0.0583

AC:

123

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

354

708

1061

1415

1769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0294

Hom.:

602

Bravo

AF:

0.0563

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.109

AC:

328

ESP6500EA

AF:

0.0170

AC:

ExAC

AF:

0.0320

AC:

3771

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

0.092

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.76

CADD

Benign

9.5

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.15

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

PhyloP100

-0.81

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.022

Sift

Benign

0.14

Sift4G

Benign

0.26

Polyphen

0.011

Vest4

0.078

MPC

0.20

ClinPred

0.0070

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.061

gMVP

0.067

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over