rs61739410

Positions:

chr6-15533238-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBA1

The NM_032122.5(DTNBP1):c.667+2C>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,613,486 control chromosomes in the GnomAD database, including 286 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 145 hom., cov: 31)

Exomes 𝑓: 0.0027 ( 141 hom. )

Consequence

DTNBP1
NM_032122.5 splice_donor

Scores

Splicing: ADA: 0.0001432

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.43

Variant links:

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 links:

LOC105374947 (HGNC:):

LOC105374947 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1467803 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 0 (no position change), new splice context is: gagGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 6-15533238-G-A is Benign according to our data. Variant chr6-15533238-G-A is described in ClinVar as [Benign]. Clinvar id is 226619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-15533238-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTNBP1	NM_032122.5 linkuse as main transcript	c.667+2C>T		splice_donor_variant		ENST00000344537.10
LOC105374947	XR_007059475.1 linkuse as main transcript	n.6115G>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTNBP1	ENST00000344537.10 linkuse as main transcript	c.667+2C>T		splice_donor_variant		1	NM_032122.5	P1	Q96EV8-1

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

3637

AN:

152026

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0817

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.00732

AC:

1838

AN:

251232

Hom.:

AF XY:

0.00554

AC XY:

752

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0873

Gnomad AMR exome

AF:

0.00573

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00346

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00273

AC:

3989

AN:

1461344

Hom.:

141

Cov.:

AF XY:

0.00254

AC XY:

1846

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.0825

Gnomad4 AMR exome

AF:

0.00572

Gnomad4 ASJ exome

AF:

0.00448

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00379

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.00525

GnomAD4 genome

AF:

0.0239

AC:

3636

AN:

152142

Hom.:

145

Cov.:

AF XY:

0.0234

AC XY:

1743

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0815

Gnomad4 AMR

AF:

0.0102

Gnomad4 ASJ

AF:

0.00289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.00567

Hom.:

Bravo

AF:

0.0270

ESP6500AA

AF:

0.0883

AC:

389

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00897

AC:

1089

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2022	Variant summary: DTNBP1 c.667+2C>T is located in a canonical splice-site. Several computational tools predict the variant strengthens/creates a canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0073 in 251232 control chromosomes, predominantly at a frequency of 0.087 within the African or African-American subpopulation in the gnomAD database, including 75 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 550-fold of the estimated maximal expected allele frequency for a pathogenic variant in DTNBP1 causing Hermansky-Pudlak Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.667+2C>T in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 12, 2015	c.667+2C>T in intron 8 of DTNBP1: This variant is not expected to have clinical significance because it has been identified in 8.9% (920/10324) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs61739410). -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.67

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.73

MutationTaster

Benign

1.0

D;D;D;D;D

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over