5-71461958-CTTTTTTTTTTTTT-CTTTTTTTTT

Variant names:

• chr5-71461958-CTTTT-C
• rs370261571
• NM_018429.3:c.599+50_599+53delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018429.3(BDP1):​c.599+50_599+53delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00584 in 440,424 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000092 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0078 (0 hom.)
• Consequence: BDP1 NM_018429.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 0 publications found

Genes affected

BDP1 (HGNC:13652): (B double prime 1, subunit of RNA polymerase III transcription initiation factor IIIB) The product of this gene is a subunit of the TFIIIB transcription initiation complex, which recruits RNA polymerase III to target promoters in order to initiate transcription. The encoded protein localizes to concentrated aggregates in the nucleus, and is required for transcription from all three types of polymerase III promoters. It is phosphorylated by casein kinase II during mitosis, resulting in its release from chromatin and suppression of polymerase III transcription. [provided by RefSeq, Jul 2008]

BDP1 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive 112

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the MID (0.00924) population. However there is too low homozygotes in high coverage region: (expected more than 3, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018429.3. 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
	BDP1	NM_018429.3	MANE Select	c.599+50_599+53delTTTT		intron	N/A	NP_060899.2	A6H8Y1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BDP1	ENST00000358731.9	TSL:1 MANE Select	c.599+33_599+36delTTTT		intron	N/A	ENSP00000351575.4	A6H8Y1-1
	BDP1	ENST00000508917.6	TSL:1	n.791+33_791+36delTTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000917 AC: 1 AN: 109070 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000174

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00776 AC: 2570 AN: 331354 Hom.: 0 AF XY: 0.00728 AC XY: 1322 AN XY: 181668

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

African (AFR) AF: 0.0111 AC: 93 AN: 8416

American (AMR) AF: 0.00810 AC: 126 AN: 15548

Ashkenazi Jewish (ASJ) AF: 0.00657 AC: 57 AN: 8676

East Asian (EAS) AF: 0.00841 AC: 137 AN: 16282

South Asian (SAS) AF: 0.00555 AC: 229 AN: 41226

European-Finnish (FIN) AF: 0.00747 AC: 155 AN: 20750

Middle Eastern (MID) AF: 0.0134 AC: 15 AN: 1120

European-Non Finnish (NFE) AF: 0.00795 AC: 1616 AN: 203214

Other (OTH) AF: 0.00881 AC: 142 AN: 16122

⚠️ 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 AF: 0.00000917 AC: 1 AN: 109070 Hom.: 0 Cov.: 0 AF XY: 0.0000202 AC XY: 1 AN XY: 49494

African (AFR) AF: 0.00 AC: 0 AN: 28858

American (AMR) AF: 0.00 AC: 0 AN: 8082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3050

East Asian (EAS) AF: 0.00 AC: 0 AN: 3756

South Asian (SAS) AF: 0.00 AC: 0 AN: 3290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 164

European-Non Finnish (NFE) AF: 0.0000174 AC: 1 AN: 57332

Other (OTH) AF: 0.00 AC: 0 AN: 1424

Alfa AF: 0.00 Hom.: 909

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs370261571; hg19: chr5-70757785;