5-71461958-CTTTTTTTTTTTTT-CTTTTTTTTTTT

Variant names:

• chr5-71461958-CTT-C
• rs370261571
• NM_018429.3:c.599+52_599+53delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_018429.3(BDP1):​c.599+52_599+53delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 434,326 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 0)
  • Exomes 𝑓: 0.043 (0 hom.)
• Consequence: BDP1 NM_018429.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: PanelApp Australia, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the AFR (0.0559) population. However there is too low homozygotes in high coverage region: (expected more than 111, got 0).
• BP6: Variant 5-71461958-CTT-C is Benign according to our data. Variant chr5-71461958-CTT-C is described in ClinVar as Benign. ClinVar VariationId is 1183277.Status of the report is criteria_provided_single_submitter, 1 stars.

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+52_599+53delTT		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+34delTT		intron	N/A	ENSP00000351575.4	A6H8Y1-1
	BDP1	ENST00000508917.6	TSL:1	n.791+33_791+34delTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 58 AN: 109070 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000495

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000440

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000349

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0415 AC: 1957 AN: 47180 AF XY: 0.0393

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.0536

Gnomad ASJ exome AF: 0.0433

Gnomad EAS exome AF: 0.0477

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0326

Gnomad OTH exome AF: 0.0467

GnomAD4 exome AF: 0.0427 AC: 13879 AN: 325272 Hom.: 0 AF XY: 0.0419 AC XY: 7473 AN XY: 178334

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

African (AFR) AF: 0.0603 AC: 496 AN: 8224

American (AMR) AF: 0.0462 AC: 704 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0428 AC: 365 AN: 8538

East Asian (EAS) AF: 0.0451 AC: 725 AN: 16064

South Asian (SAS) AF: 0.0402 AC: 1610 AN: 40038

European-Finnish (FIN) AF: 0.0332 AC: 680 AN: 20474

Middle Eastern (MID) AF: 0.0411 AC: 45 AN: 1094

European-Non Finnish (NFE) AF: 0.0427 AC: 8527 AN: 199818

Other (OTH) AF: 0.0461 AC: 727 AN: 15786

⚠️ 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: 0.000532 AC: 58 AN: 109054 Hom.: 0 Cov.: 0 AF XY: 0.000545 AC XY: 27 AN XY: 49508

African (AFR) AF: 0.00177 AC: 51 AN: 28890

American (AMR) AF: 0.000495 AC: 4 AN: 8086

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3742

South Asian (SAS) AF: 0.00 AC: 0 AN: 3268

European-Finnish (FIN) AF: 0.000440 AC: 1 AN: 2272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 150

European-Non Finnish (NFE) AF: 0.0000349 AC: 2 AN: 57324

Other (OTH) AF: 0.00 AC: 0 AN: 1430

Alfa AF: 0.00 Hom.: 909

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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)		0.040		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;