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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014641.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDC1	NM_014641.3	MANE Select	c.1157C>T	p.Pro386Leu	missense	Exon 5 of 15	NP_055456.2	Q14676-1
	MDC1-AS1	NR_133647.1		n.339G>A		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDC1	ENST00000376406.8	TSL:5 MANE Select	c.1157C>T	p.Pro386Leu	missense	Exon 5 of 15	ENSP00000365588.3	Q14676-1
MDC1	ENST00000939654.1		c.1157C>T	p.Pro386Leu	missense	Exon 6 of 16	ENSP00000609713.1
MDC1	ENST00000939657.1		c.1157C>T	p.Pro386Leu	missense	Exon 5 of 14	ENSP00000609716.1

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over