chr22-38538601-T-C

Variant names:

• chr22-38538601-T-C
• rs2227914
• NM_007068.4:c.598A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007068.4(DMC1):​c.598A>G​(p.Met200Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 1,613,802 control chromosomes in the GnomAD database, including 549 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (267 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (282 hom.)
• Consequence: DMC1 NM_007068.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.61
• Publications: 17 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025418699).
• BP6: Variant 22-38538601-T-C is Benign according to our data. Variant chr22-38538601-T-C is described in ClinVar as Benign. ClinVar VariationId is 979158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

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.598A>G	p.Met200Val	missense	Exon 10 of 14	NP_008999.2
	DMC1	NM_001278208.2		c.433A>G	p.Met145Val	missense	Exon 7 of 11	NP_001265137.1	Q14565-2
	DMC1	NM_001363017.2		c.433A>G	p.Met145Val	missense	Exon 8 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.598A>G	p.Met200Val	missense	Exon 10 of 14	ENSP00000216024.2	Q14565-1
	DMC1	ENST00000957689.1		c.598A>G	p.Met200Val	missense	Exon 11 of 15	ENSP00000627748.1
	DMC1	ENST00000911577.1		c.577A>G	p.Met193Val	missense	Exon 10 of 14	ENSP00000581636.1

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5074 AN: 152176 Hom.: 268 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.00863 AC: 2166 AN: 251050 AF XY: 0.00620

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00330 AC: 4824 AN: 1461508 Hom.: 282 Cov.: 31 AF XY: 0.00274 AC XY: 1991 AN XY: 727070

African (AFR) AF: 0.123 AC: 4098 AN: 33440

American (AMR) AF: 0.00494 AC: 221 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0000783 AC: 87 AN: 1111772

Other (OTH) AF: 0.00642 AC: 388 AN: 60392

GnomAD4 genome AF: 0.0333 AC: 5076 AN: 152294 Hom.: 267 Cov.: 32 AF XY: 0.0315 AC XY: 2346 AN XY: 74462

African (AFR) AF: 0.117 AC: 4848 AN: 41544

American (AMR) AF: 0.0104 AC: 159 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68038

Other (OTH) AF: 0.0241 AC: 51 AN: 2112

Alfa AF: 0.0186 Hom.: 261

Bravo AF: 0.0379

ESP6500AA AF: 0.114 AC: 503

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0105 AC: 1274

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Premature ovarian failure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.44
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.20
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.0040	B
Vest4		0.82
MPC		0.58
ClinPred		0.058	T
GERP RS		5.6
Varity_R		0.51
gMVP		0.79
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs2227914; hg19: chr22-38934606;