22-38521701-G-T

Variant names:

• chr22-38521701-G-T
• rs2145771075
• NM_007068.4:c.860C>A

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.860C>A​(p.Pro287His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: DMC1 NM_007068.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.47
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 22-38521701-G-T is Pathogenic according to our data. Variant chr22-38521701-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1328945.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.860C>A	p.Pro287His	missense	Exon 13 of 14	NP_008999.2
	DMC1	NM_001278208.2		c.695C>A	p.Pro232His	missense	Exon 10 of 11	NP_001265137.1	Q14565-2
	DMC1	NM_001363017.2		c.695C>A	p.Pro232His	missense	Exon 11 of 12	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.860C>A	p.Pro287His	missense	Exon 13 of 14	ENSP00000216024.2	Q14565-1
	DMC1	ENST00000957689.1		c.860C>A	p.Pro287His	missense	Exon 14 of 15	ENSP00000627748.1
	DMC1	ENST00000911577.1		c.839C>A	p.Pro280His	missense	Exon 13 of 14	ENSP00000581636.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Azoospermia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.59		Loss of ubiquitination at K286 (P = 0.0453)
MVP		0.94
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.77
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2145771075; hg19: chr22-38917706;