rs3094093

chr6-30711851-T-Achr6-30711851-T-Cchr6-30711851-T-G

Variant summary

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

The NM_014641.3(MDC1):c.2068+23A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.939 in 1,539,230 control chromosomes in the GnomAD database, including 679,468 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.96 (70048 hom., cov: 32)
  • Exomes 𝑓: 0.94 (609420 hom.)
• Consequence: MDC1 NM_014641.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.321

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.98 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDC1	NM_014641.3	c.2068+23A>T		intron_variant		ENST00000376406.8
MDC1-AS1	NR_133647.1	n.128-461T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDC1	ENST00000376406.8	c.2068+23A>T		intron_variant		5	NM_014641.3	P1
MDC1-AS1	ENST00000442150.1	n.128-461T>A		intron_variant, non_coding_transcript_variant		3
MDC1	ENST00000417033.1	c.41+23A>T		intron_variant		2
MDC1	ENST00000494654.1	n.58+23A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.959 AC: 145887 AN: 152192 Hom.: 69989 Cov.: 32

Gnomad AFR AF: 0.988

Gnomad AMI AF: 0.988

Gnomad AMR AF: 0.965

Gnomad ASJ AF: 0.993

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.944

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.966

GnomAD3 exomes AF: 0.959 AC: 184311 AN: 192116 Hom.: 88528 AF XY: 0.960 AC XY: 98491 AN XY: 102564

Gnomad AFR exome AF: 0.989

Gnomad AMR exome AF: 0.976

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.999

Gnomad FIN exome AF: 0.941

Gnomad NFE exome AF: 0.936

Gnomad OTH exome AF: 0.954

GnomAD4 exome AF: 0.937 AC: 1299569 AN: 1386920 Hom.: 609420 Cov.: 48 AF XY: 0.939 AC XY: 640195 AN XY: 681630

Gnomad4 AFR exome AF: 0.990

Gnomad4 AMR exome AF: 0.975

Gnomad4 ASJ exome AF: 0.994

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.940

Gnomad4 NFE exome AF: 0.926

Gnomad4 OTH exome AF: 0.946

GnomAD4 genome AF: 0.959 AC: 146005 AN: 152310 Hom.: 70048 Cov.: 32 AF XY: 0.959 AC XY: 71461 AN XY: 74480

Gnomad4 AFR AF: 0.988

Gnomad4 AMR AF: 0.965

Gnomad4 ASJ AF: 0.993

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 0.944

Gnomad4 NFE AF: 0.933

Gnomad4 OTH AF: 0.966

Alfa AF: 0.945 Hom.: 41706

Bravo AF: 0.962

Asia WGS AF: 0.997 AC: 3469 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	6.0
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3094093; hg19: chr6-30679628;