MDC1

protein-coding

mediator of DNA damage checkpoint 1

Gene summary

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]

MANE transcript

NM_014641.3

Inheritance

—

ClinVar variants

P:3U:219B:60

Top phenotype

Oligoasthenoteratozoospermia

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr6:30,699,807-30,717,447

External References & Databases

Ensembl (ENSG00000137337)

Transcript & Mutation Effects

hg38 • Region Span ~17.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MDC1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 233

not providedTotal: 33

OligoasthenoteratozoospermiaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014641.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	17 clinvar	5 clinvar	27
missense			211 clinvar	31 clinvar	7 clinvar	249
nonsense	2 clinvar		1 clinvar			3
start loss	1 clinvar					1
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	3	0	219	48	12	282

Highest pathogenic variant AF is 0.0000037199197

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014641.3	RefSeq	NP_055456.2	14	MANE Select
ENST00000376406.8	Ensembl	ENSP00000365588.3	14	MANE Select
ENST00000416571.5	Ensembl	ENSP00000400979.1	2	Standard
ENST00000417033.1	Ensembl	ENSP00000408962.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TP53 Regulates Transcription of DNA Repair Genes
ATM Signaling Network in Development and Disease
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
DNA Repair
Gene expression (Transcription)

Biological Process

double-strand break repair via nonhomologous end joining
intra-S DNA damage checkpoint

Molecular Function

protein binding
protein C-terminus binding
identical protein binding
FHA domain binding

Cellular Component

nucleus
nucleoplasm
chromosome
focal adhesion
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376406
Coding exons: 14
Length: 18083
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 125748
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.79	942	1.11e+3	0.849	0.0000568	13371
Missense (PolyPhen)		258	332.65	0.77559		4072
Synonymous	2.55	361	428	0.843	0.0000218	4542
Loss of Function	4.58	25	64.7	0.386	0.00000342	790

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for checkpoint mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle. May serve as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage marked by 'Ser-139' phosphorylation of histone H2AFX. Also required for downstream events subsequent to the recruitment of these proteins. These include phosphorylation and activation of the ATM, CHEK1 and CHEK2 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1. {ECO:0000269|PubMed:12475977, ECO:0000269|PubMed:12499369, ECO:0000269|PubMed:12551934, ECO:0000269|PubMed:12607003, ECO:0000269|PubMed:12607004, ECO:0000269|PubMed:12607005, ECO:0000269|PubMed:12611903, ECO:0000269|PubMed:14695167, ECO:0000269|PubMed:15201865, ECO:0000269|PubMed:15377652}.;

Intolerance Scores

LoFtool: 0.630
RVIS EVS: 5.2
RVIS percentile EVS: 99.83

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.951

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium