22-38566611-T-A

Position:

• chr22-38566611-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007068.4(DMC1):​c.222A>T​(p.Lys74Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DMC1 NM_007068.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMC1	NM_007068.4	c.222A>T	p.Lys74Asn	missense_variant	4/14	ENST00000216024.7	NP_008999.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMC1	ENST00000216024.7	c.222A>T	p.Lys74Asn	missense_variant	4/14	1	NM_007068.4	ENSP00000216024.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.222A>T (p.K74N) alteration is located in exon 4 (coding exon 3) of the DMC1 gene. This alteration results from a A to T substitution at nucleotide position 222, causing the lysine (K) at amino acid position 74 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;.;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.0	M;M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.2	D;D;D;.;D
REVEL	Benign	0.20
Sift	Benign	0.16	T;T;D;.;D
Sift4G	Benign	0.13	T;T;.;T;.
Polyphen		0.60, 0.83	.;P;.;P;.
Vest4		0.71
MutPred		0.43		Loss of ubiquitination at K74 (P = 0.0446);Loss of ubiquitination at K74 (P = 0.0446);Loss of ubiquitination at K74 (P = 0.0446);Loss of ubiquitination at K74 (P = 0.0446);Loss of ubiquitination at K74 (P = 0.0446);
MVP		0.71
MPC		1.2
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-38962616;