1-91964728-C-G

Variant names:

• chr1-91964728-C-G
• rs879020404
• NM_207189.4:c.294C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_207189.4(BRDT):​c.294C>G​(p.Phe98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000748 in 1,337,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: BRDT NM_207189.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0920
• Publications: 0 publications found

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]

BRDT Gene-Disease associations (from GenCC):

• spermatogenic failure 21

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37736118).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207189.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRDT	NM_207189.4	MANE Select	c.294C>G	p.Phe98Leu	missense	Exon 3 of 19	NP_997072.2	Q58F21-1
	BRDT	NM_001242806.2		c.294C>G	p.Phe98Leu	missense	Exon 3 of 19	NP_001229735.2	Q58F21-3
	BRDT	NM_001242805.2		c.294C>G	p.Phe98Leu	missense	Exon 4 of 20	NP_001229734.2	Q58F21-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRDT	ENST00000399546.7	TSL:2 MANE Select	c.294C>G	p.Phe98Leu	missense	Exon 3 of 19	ENSP00000387822.3	Q58F21-1
	BRDT	ENST00000362005.7	TSL:1	c.294C>G	p.Phe98Leu	missense	Exon 4 of 20	ENSP00000354568.3	Q58F21-1
	BRDT	ENST00000402388.1	TSL:1	c.294C>G	p.Phe98Leu	missense	Exon 3 of 19	ENSP00000384051.1	Q58F21-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.48e-7 AC: 1 AN: 1337014 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 657806

⚠️ 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: 30942

American (AMR) AF: 0.00 AC: 0 AN: 38800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23622

East Asian (EAS) AF: 0.00 AC: 0 AN: 38082

South Asian (SAS) AF: 0.00 AC: 0 AN: 65822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5158

European-Non Finnish (NFE) AF: 9.71e-7 AC: 1 AN: 1029422

Other (OTH) AF: 0.00 AC: 0 AN: 54732

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.67	N
PhyloP100		0.092
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.12
Sift	Benign	0.079	T
Sift4G	Uncertain	0.046	D
Polyphen		0.096	B
Vest4		0.54
MutPred		0.61		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
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs879020404; hg19: chr1-92430285;