6-30703467-C-T

Variant names:

• chr6-30703467-C-T
• rs376836775
• NM_014641.3:c.5633G>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.5633G>A​(p.Ser1878Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,970 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: -0.197

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=0.00881964).
• BP6: Variant 6-30703467-C-T is Benign according to our data. Variant chr6-30703467-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2360726.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 rank	MANE	Protein	UniProt
MDC1	NM_014641.3	c.5633G>A	p.Ser1878Asn	missense_variant	Exon 11 of 15	ENST00000376406.8	NP_055456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDC1	ENST00000376406.8	c.5633G>A	p.Ser1878Asn	missense_variant	Exon 11 of 15	5	NM_014641.3	ENSP00000365588.3
MDC1	ENST00000489540.1	n.615G>A		non_coding_transcript_exon_variant	Exon 1 of 5	2
MDC1-AS1	ENST00000442150.1	n.127+274C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152146 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: 0.000237 AC: 59 AN: 249468 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

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: 0.00000888

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1461706 Hom.: 5 Cov.: 33 AF XY: 0.000153 AC XY: 111 AN XY: 727158

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: 0.000754

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152264 Hom.: 3 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000207

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

Jun 28, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.10
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.2
DANN	Benign	0.90
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.092	N
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.026
Sift	Benign	0.22	T
Sift4G	Uncertain	0.048	D
Polyphen		0.0	B
Vest4		0.070
MutPred		0.15		Loss of phosphorylation at S1878 (P = 0.0054);
MVP		0.24
MPC		0.18
ClinPred		0.019	T
GERP RS		-1.2
Varity_R		0.015
gMVP		0.25

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: rs376836775; hg19: chr6-30671244;