chr6-15656839-G-A

Variant names:

• chr6-15656839-G-A
• rs1018381
• NM_032122.5:c.57-4699C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019): 0P and 12B. BA1BP4_Strong

The NM_032122.5(DTNBP1):c.57-4699C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.154 (AC=23,453) in the gnomAD database across 152,128 control chromosomes, including 2,700 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.312. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2700 hom., cov: 32)
• Consequence: DTNBP1 NM_032122.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 45 publications found

Genes affected

DTNBP1 (HGNC:17328): (dystrobrevin binding protein 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. A similar protein in mouse is a component of a protein complex termed biogenesis of lysosome-related organelles complex 1 (BLOC-1), and binds to alpha- and beta-dystrobrevins, which are components of the dystrophin-associated protein complex (DPC). Mutations in this gene are associated with Hermansky-Pudlak syndrome type 7. This gene may also be associated with schizophrenia. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DTNBP1 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -12 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3124 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_032122.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	NM_032122.5	MANE Select	c.57-4699C>T		intron	N/A	NP_115498.2
	DTNBP1	NM_001271668.2		c.57-4699C>T		intron	N/A	NP_001258597.1	A6NFV8
	DTNBP1	NM_001271669.2		c.56+5975C>T		intron	N/A	NP_001258598.1	A0A087WYP9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	ENST00000344537.10	TSL:1 MANE Select	c.57-4699C>T		intron	N/A	ENSP00000341680.6	Q96EV8-1
	DTNBP1	ENST00000622898.4	TSL:1	c.56+5975C>T		intron	N/A	ENSP00000481997.1	A0A087WYP9
	DTNBP1	ENST00000338950.9	TSL:1	c.57-4699C>T		intron	N/A	ENSP00000344718.5	Q96EV8-2

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23420 AN: 152010 Hom.: 2700 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.0971

Gnomad EAS AF: 0.0787

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0537

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.0844

Gnomad OTH AF: 0.146

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.154 AC: 23453 AN: 152128 Hom.: 2700 Cov.: 32 AF XY: 0.151 AC XY: 11269 AN XY: 74392

African (AFR) AF: 0.317 AC: 13134 AN: 41440

American (AMR) AF: 0.149 AC: 2281 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0971 AC: 337 AN: 3470

East Asian (EAS) AF: 0.0791 AC: 410 AN: 5184

South Asian (SAS) AF: 0.117 AC: 566 AN: 4822

European-Finnish (FIN) AF: 0.0537 AC: 569 AN: 10588

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.0844 AC: 5741 AN: 68012

Other (OTH) AF: 0.147 AC: 310 AN: 2108

Alfa AF: 0.0920 Hom.: 502

Bravo AF: 0.169

Asia WGS AF: 0.116 AC: 405 AN: 3478

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.0681 AC: 8356 AN: 122766

Turkish Variome AF: 0.0724 AC: 112 AN: 1546 Hom.: 4

WBBC (Westlake BioBank for Chinese) pilot AF: 0.0816 AC: 731 AN: 8960 Hom.: 47

ABraOM SABE-WGS-1171 AF: 0.149 AC: 348 AN: 2342 Hom.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.033
DANN	Benign	0.70
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1018381;

hg19: chr6-15657070;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar