rs9461623

Positions:

• chr6-30705645-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014641.3(MDC1):​c.3538T>C​(p.Ser1180Pro) 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 1,583,612 control chromosomes in the GnomAD database, including 1,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.051 (295 hom., cov: 30)
  • Exomes 𝑓: 0.021 (770 hom.)
• Consequence: MDC1 NM_014641.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.741

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016266108).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDC1	NM_014641.3	c.3538T>C	p.Ser1180Pro	missense_variant	10/15	ENST00000376406.8	NP_055456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDC1	ENST00000376406.8	c.3538T>C	p.Ser1180Pro	missense_variant	10/15	5	NM_014641.3	ENSP00000365588.3
MDC1	ENST00000417033.1	c.718T>C	p.Ser240Pro	missense_variant	5/5	2		ENSP00000408962.1
MDC1	ENST00000492462.1	n.756T>C		non_coding_transcript_exon_variant	2/2	3
MDC1-AS1	ENST00000442150.1	n.127+2452A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7159 AN: 140116 Hom.: 295 Cov.: 30

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.0111

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0624

Gnomad EAS AF: 0.0668

Gnomad SAS AF: 0.0264

Gnomad FIN AF: 0.00729

Gnomad MID AF: 0.0880

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0620

GnomAD3 exomes AF: 0.0331 AC: 7672 AN: 231550 Hom.: 186 AF XY: 0.0318 AC XY: 3990 AN XY: 125310

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0354

Gnomad ASJ exome AF: 0.0686

Gnomad EAS exome AF: 0.0620

Gnomad SAS exome AF: 0.0313

Gnomad FIN exome AF: 0.00646

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0210 AC: 30265 AN: 1443374 Hom.: 770 Cov.: 35 AF XY: 0.0211 AC XY: 15121 AN XY: 717486

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.0370

Gnomad4 ASJ exome AF: 0.0659

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.0296

Gnomad4 FIN exome AF: 0.00692

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0290

GnomAD4 genome AF: 0.0511 AC: 7166 AN: 140238 Hom.: 295 Cov.: 30 AF XY: 0.0504 AC XY: 3467 AN XY: 68766

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0491

Gnomad4 ASJ AF: 0.0624

Gnomad4 EAS AF: 0.0669

Gnomad4 SAS AF: 0.0260

Gnomad4 FIN AF: 0.00729

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0608

Alfa AF: 0.0327 Hom.: 83

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.111 AC: 491

ESP6500EA AF: 0.0160 AC: 138

ExAC AF: 0.0321 AC: 3896

Asia WGS AF: 0.0410 AC: 143 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.059
DANN	Benign	0.73
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0011	N
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.7	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.025
Sift	Benign	1.0	T
Sift4G	Benign	0.97	T
Polyphen		0.0010	B
Vest4		0.0080
MPC		0.25
ClinPred		0.0014	T
GERP RS		-4.6
Varity_R		0.042
gMVP		0.052

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: rs9461623; hg19: chr6-30673422; COSMIC: COSV64527968; COSMIC: COSV64527968;