1-53459620-T-G

Variant names:

• chr1-53459620-T-G
• rs768540318
• NM_033067.3:c.167T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033067.3(DMRTB1):​c.167T>G​(p.Leu56Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,424,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: DMRTB1 NM_033067.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19

Genes affected

DMRTB1 (HGNC:13913): (DMRT like family B with proline rich C-terminal 1) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in germ cell development; regulation of transcription by RNA polymerase II; and sex differentiation. 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMRTB1	NM_033067.3	c.167T>G	p.Leu56Arg	missense_variant	Exon 1 of 4	ENST00000371445.3	NP_149056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMRTB1	ENST00000371445.3	c.167T>G	p.Leu56Arg	missense_variant	Exon 1 of 4	1	NM_033067.3	ENSP00000360500.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000112 AC: 16 AN: 1424178 Hom.: 0 Cov.: 30 AF XY: 0.00000709 AC XY: 5 AN XY: 705100

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000146

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.167T>G (p.L56R) alteration is located in exon 1 (coding exon 1) of the DMRTB1 gene. This alteration results from a T to G substitution at nucleotide position 167, causing the leucine (L) at amino acid position 56 to be replaced by an arginine (R). 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	0.75
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.50		Gain of helix (P = 6e-04);
MVP		0.71
MPC		1.6
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.84
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs768540318; hg19: chr1-53925293;