22-38539368-T-C

Variant names:

• chr22-38539368-T-C
• rs996254937
• NM_007068.4:c.539A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007068.4(DMC1):​c.539A>G​(p.Asp180Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DMC1 NM_007068.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80
• Publications: 0 publications found

Genes affected

DMC1 (HGNC:2927): (DNA meiotic recombinase 1) This gene encodes a member of the superfamily of recombinases (also called DNA strand-exchange proteins). Recombinases are important for repairing double-strand DNA breaks during mitosis and meiosis. This protein, which is evolutionarily conserved, is reported to be essential for meiotic homologous recombination and may thus play an important role in generating diversity of genetic information. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

DMC1 Gene-Disease associations (from GenCC):

• spermatogenic failure

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007068.4. 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
	DMC1	NM_007068.4	MANE Select	c.539A>G	p.Asp180Gly	missense	Exon 9 of 14	NP_008999.2
	DMC1	NM_001278208.2		c.422-756A>G		intron	N/A	NP_001265137.1	Q14565-2
	DMC1	NM_001363017.2		c.422-756A>G		intron	N/A	NP_001349946.1	Q14565-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMC1	ENST00000216024.7	TSL:1 MANE Select	c.539A>G	p.Asp180Gly	missense	Exon 9 of 14	ENSP00000216024.2	Q14565-1
	DMC1	ENST00000957689.1		c.539A>G	p.Asp180Gly	missense	Exon 10 of 15	ENSP00000627748.1
	DMC1	ENST00000911577.1		c.518A>G	p.Asp173Gly	missense	Exon 9 of 14	ENSP00000581636.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.014	D
Polyphen		0.94	P
Vest4		0.93
MutPred		0.66		Loss of helix (P = 0.0123)
MVP		0.78
MPC		1.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.89
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs996254937; hg19: chr22-38935373;