Genetic Variant MDC1:p.Pro1822Ser (chr6-30703719-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_014641.3(MDC1):c.5464C>T(p.Pro1822Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,540,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

MDC1
NM_014641.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02

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:

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=0.23692307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDC1	NM_014641.3 link	c.5464C>T	p.Pro1822Ser	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.5464C>T	p.Pro1822Ser	missense_variant	Exon 10 of 15	5	NM_014641.3	ENSP00000365588.3	Q14676-1
MDC1	ENST00000489540.1 link	n.363C>T		non_coding_transcript_exon_variant	Exon 1 of 5	2
MDC1-AS1	ENST00000442150.1 link	n.127+526G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

187768

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000193

Gnomad AMR exome

AF:

0.00

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:

0.00000648

AC:

AN:

1388638

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

684274

show subpopulations

African (AFR)

AF:

0.000292

AC:

AN:

30804

American (AMR)

AF:

0.00

AC:

AN:

32026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20864

East Asian (EAS)

AF:

0.00

AC:

AN:

39300

South Asian (SAS)

AF:

0.00

AC:

AN:

72404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5382

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080348

Other (OTH)

AF:

0.00

AC:

AN:

57188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Dec 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5464C>T (p.P1822S) alteration is located in exon 10 (coding exon 9) of the MDC1 gene. This alteration results from a C to T substitution at nucleotide position 5464, causing the proline (P) at amino acid position 1822 to be replaced by a serine (S). 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

0.094

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.83

M_CAP

Benign

0.0029

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

PhyloP100

3.0

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.10

Sift

Pathogenic

0.0

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.22

MutPred

0.26

Loss of glycosylation at P1822 (P = 0.0123);

MVP

0.63

MPC

0.77

ClinPred

0.97

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.069

gMVP

0.27

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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6-30703719-G-A

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