22-38539380-C-T

Variant names:

• chr22-38539380-C-T
• rs745833596
• NM_007068.4:c.527G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007068.4(DMC1):​c.527G>A​(p.Arg176His) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,854 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: DMC1 NM_007068.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3983659).

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.527G>A	p.Arg176His	missense	Exon 9 of 14	NP_008999.2
	DMC1	NM_001278208.2		c.422-768G>A		intron	N/A	NP_001265137.1	Q14565-2
	DMC1	NM_001363017.2		c.422-768G>A		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.527G>A	p.Arg176His	missense	Exon 9 of 14	ENSP00000216024.2	Q14565-1
	DMC1	ENST00000957689.1		c.527G>A	p.Arg176His	missense	Exon 10 of 15	ENSP00000627748.1
	DMC1	ENST00000911577.1		c.506G>A	p.Arg169His	missense	Exon 9 of 14	ENSP00000581636.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251456 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.000163

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461718 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727156

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111894

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.000131 AC: 2 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	0.50
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.032	D
Polyphen		0.45	B
Vest4		0.38
MutPred		0.54		Loss of helix (P = 0.0795)
MVP		0.74
MPC		0.76
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.88
gMVP		0.82
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs745833596; hg19: chr22-38935385;