5-71461958-CTTT-C

Variant names:

• chr5-71461958-CTTT-C
• rs370261571
• NM_018429.3:c.599+51_599+53delTTT

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+51_599+53delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 437,266 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., cov: 0)
  • Exomes 𝑓: 0.019 (0 hom.)
• Consequence: BDP1 NM_018429.3 intron
• Clinical Significance: Likely 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 (0.0239) population. However there is too low homozygotes in high coverage region: (expected more than 22, got 0).
• BP6: Variant 5-71461958-CTTT-C is Benign according to our data. Variant chr5-71461958-CTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1317595.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+51_599+53delTTT		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+35delTTT		intron	N/A	ENSP00000351575.4	A6H8Y1-1
	BDP1	ENST00000508917.6	TSL:1	n.791+33_791+35delTTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000550 AC: 6 AN: 109062 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000304

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000349

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0181 AC: 855 AN: 47180 AF XY: 0.0172

Gnomad AFR exome AF: 0.0221

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.0212

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0193 AC: 6324 AN: 328204 Hom.: 0 AF XY: 0.0189 AC XY: 3395 AN XY: 179914

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

African (AFR) AF: 0.0268 AC: 224 AN: 8350

American (AMR) AF: 0.0211 AC: 324 AN: 15378

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 166 AN: 8572

East Asian (EAS) AF: 0.0207 AC: 335 AN: 16158

South Asian (SAS) AF: 0.0168 AC: 683 AN: 40614

European-Finnish (FIN) AF: 0.0156 AC: 322 AN: 20588

Middle Eastern (MID) AF: 0.0210 AC: 23 AN: 1094

European-Non Finnish (NFE) AF: 0.0194 AC: 3916 AN: 201472

Other (OTH) AF: 0.0207 AC: 331 AN: 15978

⚠️ 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: 0.0000550 AC: 6 AN: 109062 Hom.: 0 Cov.: 0 AF XY: 0.0000404 AC XY: 2 AN XY: 49492

African (AFR) AF: 0.000104 AC: 3 AN: 28858

American (AMR) AF: 0.00 AC: 0 AN: 8080

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3758

South Asian (SAS) AF: 0.000304 AC: 1 AN: 3290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2264

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

European-Non Finnish (NFE) AF: 0.0000349 AC: 2 AN: 57330

Other (OTH) AF: 0.00 AC: 0 AN: 1426

Alfa AF: 0.00 Hom.: 909

ClinVar

ClinVar submissions as Germline

Significance: Likely 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)		0.020		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;