6-30703639-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014641.3(MDC1):c.5544G>C(p.Glu1848Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,585,302 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 1 hom. )

Consequence

MDC1
NM_014641.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.454

Publications

2 publications found

Variant links:

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 links:

MDC1-AS1 (HGNC:39764): (MDC1 antisense RNA 1)

MDC1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.08551532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDC1	NM_014641.3 link	c.5544G>C	p.Glu1848Asp	missense_variant	Exon 10 of 15	ENST00000376406.8	NP_055456.2	Q14676-1A0A1U9XBC1A1Z5I9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MDC1	ENST00000376406.8 link	c.5544G>C	p.Glu1848Asp	missense_variant	Exon 10 of 15	5	NM_014641.3	ENSP00000365588.3	Q14676-1
MDC1	ENST00000489540.1 link	n.443G>C		non_coding_transcript_exon_variant	Exon 1 of 5	2
MDC1-AS1	ENST00000442150.1 link	n.127+446C>G		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000313

AC:

AN:

223718

AF XY:

0.0000332

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000237

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000133

AC:

AN:

1433082

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

711452

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31906

American (AMR)

AF:

0.000406

AC:

AN:

39404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24002

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.00

AC:

AN:

81540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1099696

Other (OTH)

AF:

0.0000339

AC:

AN:

59040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.000327

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5544G>C (p.E1848D) alteration is located in exon 10 (coding exon 9) of the MDC1 gene. This alteration results from a G to C substitution at nucleotide position 5544, causing the glutamic acid (E) at amino acid position 1848 to be replaced by an aspartic acid (D). 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

0.16

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.67

CADD

Benign

3.5

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.069

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.17

M_CAP

Benign

0.0030

MetaRNN

Benign

0.086

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

-0.45

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.3

REVEL

Benign

0.044

Sift

Benign

0.057

Sift4G

Benign

0.22

Polyphen

0.67

Vest4

0.097

MutPred

0.20

Loss of methylation at K1849 (P = 0.0897);

MVP

0.48

MPC

0.22

ClinPred

0.10

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.033

gMVP

0.22

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

6-30703639-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over