rs2075015

chr6-30712831-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

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. 12/19 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.049 (359 hom., cov: 32)
  • Exomes 𝑓: 0.021 (917 hom.)
• Consequence: MDC1 NM_014641.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.127

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

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MDC1
• 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/exons	MANE	UniProt
MDC1	NM_014641.3	c.1111G>A	p.Glu371Lys	missense_variant	5/15	ENST00000376406.8
MDC1-AS1	NR_133647.1	n.385C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDC1	ENST00000376406.8	c.1111G>A	p.Glu371Lys	missense_variant	5/15	5	NM_014641.3	P1
MDC1-AS1	ENST00000442150.1	n.385C>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0485 AC: 7384 AN: 152184 Hom.: 359 Cov.: 32

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

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.: 38 AF XY: 0.0212 AC XY: 15390 AN XY: 726664

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.: 32 AF XY: 0.0480 AC XY: 3575 AN XY: 74476

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: 47

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.108 AC: 325

ESP6500EA AF: 0.0168 AC: 91

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	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.039	N
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.056
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.064	T
Polyphen		0.82	P
Vest4		0.10
MPC		0.80
ClinPred		0.014	T
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

Other links and lift over

dbSNP: rs2075015; hg19: chr6-30680608; COSMIC: COSV64523332; COSMIC: COSV64523332;