Variant 6-30704051-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_014641.3(MDC1):c.5132C>T(p.Ser1711Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1711Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MDC1
NM_014641.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.25

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity MDC1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15579283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDC1	NM_014641.3 linkuse as main transcript	c.5132C>T	p.Ser1711Phe	missense_variant	10/15	ENST00000376406.8
MDC1-AS1	NR_133647.1 linkuse as main transcript	n.127+858G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDC1	ENST00000376406.8 linkuse as main transcript	c.5132C>T	p.Ser1711Phe	missense_variant	10/15	5	NM_014641.3	P1	Q14676-1
MDC1-AS1	ENST00000442150.1 linkuse as main transcript	n.127+858G>A		intron_variant, non_coding_transcript_variant		3
MDC1	ENST00000489540.1 linkuse as main transcript	n.31C>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.23

M_CAP

Benign

0.0058

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.11

Sift

Uncertain

0.021

Sift4G

Uncertain

0.029

Polyphen

0.99

Vest4

0.19

MutPred

0.26

Loss of glycosylation at S1711 (P = 0.0038);

MVP

0.46

MPC

0.49

ClinPred

0.88

GERP RS

3.5

Varity_R

0.023

gMVP

0.12

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over