9-990154-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021240.4(DMRT3):c.568T>C(p.Phe190Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DMRT3 NM_021240.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15705615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMRT3	NM_021240.4	c.568T>C	p.Phe190Leu	missense_variant	2/2	ENST00000190165.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMRT3	ENST00000190165.3	c.568T>C	p.Phe190Leu	missense_variant	2/2	1	NM_021240.4	P1
DMRT3	ENST00000417254.1	c.157T>C	p.Phe53Leu	missense_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jun 24, 2022

The c.568T>C (p.F190L) alteration is located in exon 2 (coding exon 2) of the DMRT3 gene. This alteration results from a T to C substitution at nucleotide position 568, causing the phenylalanine (F) at amino acid position 190 to be replaced by a leucine (L). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	16
Dann	Benign	0.87
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;D
REVEL	Benign	0.075
Sift	Benign	0.35	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0010	B;.
Vest4		0.12
MutPred		0.18		Gain of glycosylation at S186 (P = 0.1457);.;
MVP		0.55
MPC		0.10
ClinPred		0.46	T
GERP RS		4.9
Varity_R		0.18
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-990154;