chr1-91964728-C-A

Position:

• chr1-91964728-C-A

Variant summary

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

The NM_207189.4(BRDT):​c.294C>A​(p.Phe98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,337,014 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: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: BRDT NM_207189.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0920

Genes affected

BRDT (HGNC:1105): (bromodomain testis associated) BRDT is similar to the RING3 protein family. It possesses 2 bromodomain motifs and a PEST sequence (a cluster of proline, glutamic acid, serine, and threonine residues), characteristic of proteins that undergo rapid intracellular degradation. The bromodomain is found in proteins that regulate transcription. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

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	UniProt
BRDT	NM_207189.4	c.294C>A	p.Phe98Leu	missense_variant	3/19	ENST00000399546.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRDT	ENST00000399546.7	c.294C>A	p.Phe98Leu	missense_variant	3/19	2	NM_207189.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000374 AC: 5 AN: 1337014 Hom.: 0 Cov.: 28 AF XY: 0.00000608 AC XY: 4 AN XY: 657806

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: 0.0000760

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Mar 22, 2023

The c.294C>A (p.F98L) alteration is located in exon 3 (coding exon 2) of the BRDT gene. This alteration results from a C to A substitution at nucleotide position 294, causing the phenylalanine (F) at amino acid position 98 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	Pathogenic	0.60
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.;.;.;.;.;T;.;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.67	N;.;N;.;.;.;.;.;.;.;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.12
Sift	Benign	0.079	T;T;T;T;T;T;T;D;T;T;T
Sift4G	Uncertain	0.046	D;T;D;T;T;T;T;T;T;T;D
Polyphen		0.096	B;.;.;.;.;.;.;.;.;.;B
Vest4		0.54
MutPred		0.61		Loss of catalytic residue at F98 (P = 0.0389);.;Loss of catalytic residue at F98 (P = 0.0389);Loss of catalytic residue at F98 (P = 0.0389);Loss of catalytic residue at F98 (P = 0.0389);Loss of catalytic residue at F98 (P = 0.0389);Loss of catalytic residue at F98 (P = 0.0389);Loss of catalytic residue at F98 (P = 0.0389);Loss of catalytic residue at F98 (P = 0.0389);.;Loss of catalytic residue at F98 (P = 0.0389);
MVP		0.34
MPC		0.25
ClinPred		0.99	D
GERP RS		-2.9
Varity_R		0.78
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 36

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

Publications

LitVar

Other links and lift over

dbSNP: rs879020404; hg19: chr1-92430285;