9-977365-C-T

Position:

• chr9-977365-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021240.4(DMRT3):​c.364C>T​(p.Arg122Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,081,810 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: DMRT3 NM_021240.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.146

Genes affected

DMRT3 (HGNC:13909): (doublesex and mab-3 related transcription factor 3) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in male sex differentiation and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including adult walking behavior; transmission of nerve impulse; and ventral spinal cord interneuron specification. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35041815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMRT3	NM_021240.4	c.364C>T	p.Arg122Cys	missense_variant	1/2	ENST00000190165.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMRT3	ENST00000190165.3	c.364C>T	p.Arg122Cys	missense_variant	1/2	1	NM_021240.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1081810 Hom.: 0 Cov.: 31 AF XY: 0.00000194 AC XY: 1 AN XY: 515060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000477

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Oct 30, 2023

The c.364C>T (p.R122C) alteration is located in exon 1 (coding exon 1) of the DMRT3 gene. This alteration results from a C to T substitution at nucleotide position 364, causing the arginine (R) at amino acid position 122 to be replaced by a cysteine (C). 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	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.036
Eigen_PC	Benign	0.039
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.064	T
Polyphen		0.98	D
Vest4		0.42
MutPred		0.23		Gain of catalytic residue at P121 (P = 0.0365);
MVP		0.70
MPC		0.14
ClinPred		0.81	D
GERP RS		3.8
Varity_R		0.20
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs891913305; hg19: chr9-977365;