6-30703970-T-A

Position:

• chr6-30703970-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014641.3(MDC1):​c.5213A>T​(p.Asp1738Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,614,132 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (5 hom.)
• Consequence: MDC1 NM_014641.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.12

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00658229).
• BP6: Variant 6-30703970-T-A is Benign according to our data. Variant chr6-30703970-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2360788.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDC1	NM_014641.3	c.5213A>T	p.Asp1738Val	missense_variant	10/15	ENST00000376406.8
MDC1-AS1	NR_133647.1	n.127+777T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDC1	ENST00000376406.8	c.5213A>T	p.Asp1738Val	missense_variant	10/15	5	NM_014641.3	P1
MDC1-AS1	ENST00000442150.1	n.127+777T>A		intron_variant, non_coding_transcript_variant		3
MDC1	ENST00000489540.1	n.112A>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251384 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000166 AC: 242 AN: 1461874 Hom.: 5 Cov.: 34 AF XY: 0.000150 AC XY: 109 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000856

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152258 Hom.: 3 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.061
DANN	Benign	0.73
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.017	N
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.28	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.016
Sift	Benign	0.43	T
Sift4G	Benign	0.31	T
Polyphen		0.0070	B
Vest4		0.066
MutPred		0.22		Gain of methylation at K1740 (P = 0.0365);
MVP		0.19
MPC		0.28
ClinPred		0.0045	T
GERP RS		-4.9
Varity_R		0.038
gMVP		0.14

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: rs376172465; hg19: chr6-30671747;