6-30703751-C-T

Variant names:

• chr6-30703751-C-T
• rs368708770
• NM_014641.3:c.5432G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014641.3(MDC1):​c.5432G>A​(p.Arg1811His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000414 in 1,547,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: MDC1 NM_014641.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.19
• Publications: 5 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032299966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDC1	NM_014641.3	c.5432G>A	p.Arg1811His	missense_variant	Exon 10 of 15	ENST00000376406.8	NP_055456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDC1	ENST00000376406.8	c.5432G>A	p.Arg1811His	missense_variant	Exon 10 of 15	5	NM_014641.3	ENSP00000365588.3
MDC1	ENST00000489540.1	n.331G>A		non_coding_transcript_exon_variant	Exon 1 of 5	2
MDC1-AS1	ENST00000442150.1	n.127+558C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000114 AC: 22 AN: 193476 AF XY: 0.000117

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000182

Gnomad FIN exome AF: 0.0000556

Gnomad NFE exome AF: 0.000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000444 AC: 62 AN: 1395196 Hom.: 0 Cov.: 33 AF XY: 0.0000407 AC XY: 28 AN XY: 688176

African (AFR) AF: 0.0000646 AC: 2 AN: 30978

American (AMR) AF: 0.00 AC: 0 AN: 33342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21288

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39328

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73660

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.0000471 AC: 51 AN: 1083106

Other (OTH) AF: 0.0000174 AC: 1 AN: 57488

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000149 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5432G>A (p.R1811H) alteration is located in exon 10 (coding exon 9) of the MDC1 gene. This alteration results from a G to A substitution at nucleotide position 5432, causing the arginine (R) at amino acid position 1811 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.8
DANN	Benign	0.93
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.043	N
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.85	L
PhyloP100		-2.2
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.027
Sift	Benign	0.18	T
Sift4G	Benign	0.25	T
Polyphen		0.072	B
Vest4		0.072
MVP		0.24
MPC		0.25
ClinPred		0.060	T
GERP RS		-0.66
Varity_R		0.028
gMVP		0.15
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368708770; hg19: chr6-30671528; COSMIC: COSV64524354; COSMIC: COSV64524354;