chr1-53459974-C-T

Variant names:

• chr1-53459974-C-T
• rs929777443
• NM_033067.3:c.521C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033067.3(DMRTB1):​c.521C>T​(p.Pro174Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,432,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DMRTB1 NM_033067.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.10

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03941703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMRTB1	NM_033067.3	c.521C>T	p.Pro174Leu	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.521C>T	p.Pro174Leu	missense_variant	Exon 1 of 4	1	NM_033067.3	ENSP00000360500.3
DMRTB1	ENST00000463126.1	n.-2C>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1432350 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712266

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32092

American (AMR) AF: 0.00 AC: 0 AN: 43966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 38452

South Asian (SAS) AF: 0.00 AC: 0 AN: 84430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5174

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106396

Other (OTH) AF: 0.00 AC: 0 AN: 59620

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001311), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.521C>T (p.P174L) alteration is located in exon 1 (coding exon 1) of the DMRTB1 gene. This alteration results from a C to T substitution at nucleotide position 521, causing the proline (P) at amino acid position 174 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	Benign	0.072
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.016
DANN	Benign	0.91
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		-2.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.60	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.071
MutPred		0.30		Loss of disorder (P = 0.0737);
MVP		0.043
MPC		0.46
ClinPred		0.063	T
GERP RS		-6.2
Varity_R		0.027
gMVP		0.091
Mutation Taster		=95/5	polymorphism

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: rs929777443; hg19: chr1-53925647; COSMIC: COSV65113117; COSMIC: COSV65113117;