Genetic Variant NM_014641.3:c.5521G>A (chr6-30703662-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014641.3(MDC1):c.5521G>A(p.Glu1841Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,405,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MDC1
NM_014641.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.596

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2227225).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014641.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDC1	NM_014641.3	MANE Select	c.5521G>A	p.Glu1841Lys	missense	Exon 10 of 15	NP_055456.2	Q14676-1
	MDC1-AS1	NR_133647.1		n.127+469C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDC1	ENST00000376406.8	TSL:5 MANE Select	c.5521G>A	p.Glu1841Lys	missense	Exon 10 of 15	ENSP00000365588.3	Q14676-1
MDC1	ENST00000939654.1		c.5521G>A	p.Glu1841Lys	missense	Exon 11 of 16	ENSP00000609713.1
MDC1	ENST00000939657.1		c.5521G>A	p.Glu1841Lys	missense	Exon 10 of 14	ENSP00000609716.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1405890

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31178

American (AMR)

AF:

0.00

AC:

AN:

34874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22144

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39390

South Asian (SAS)

AF:

0.00

AC:

AN:

75484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5450

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088330

Other (OTH)

AF:

0.00

AC:

AN:

57934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.063

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.27

M_CAP

Benign

0.0065

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

0.60

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.8

REVEL

Benign

0.049

Sift

Uncertain

0.0070

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.25

MutPred

0.30

Gain of ubiquitination at E1841 (P = 0.0014)

MVP

0.50

MPC

0.81

ClinPred

0.83

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.051

gMVP

0.35

Mutation Taster

=92/8

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over