22-38539326-T-C

Variant names:

• chr22-38539326-T-C
• rs760917211
• NM_007068.4:c.581A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_007068.4(DMC1):​c.581A>G​(p.Tyr194Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,720 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 Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DMC1 NM_007068.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.80
• Publications: 1 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 22-38539326-T-C is Pathogenic according to our data. Variant chr22-38539326-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3629600.Status of the report is no_assertion_criteria_provided, 0 stars.

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.581A>G	p.Tyr194Cys	missense	Exon 9 of 14	NP_008999.2
	DMC1	NM_001278208.2		c.422-714A>G		intron	N/A	NP_001265137.1	Q14565-2
	DMC1	NM_001363017.2		c.422-714A>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.581A>G	p.Tyr194Cys	missense	Exon 9 of 14	ENSP00000216024.2	Q14565-1
	DMC1	ENST00000957689.1		c.581A>G	p.Tyr194Cys	missense	Exon 10 of 15	ENSP00000627748.1
	DMC1	ENST00000911577.1		c.560A>G	p.Tyr187Cys	missense	Exon 9 of 14	ENSP00000581636.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251462 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460720 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726734

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Non-obstructive azoospermia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.47		Gain of helix (P = 0.0164)
MVP		0.81
MPC		1.7
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.86
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.31		Position offset: -5

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

Other links and lift over

dbSNP: rs760917211; hg19: chr22-38935331;