rs73369534

Positions:

• chr6-15523157-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032122.5(DTNBP1):​c.874A>G​(p.Arg292Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,614,228 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (162 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (132 hom.)
• Consequence: DTNBP1 NM_032122.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.01

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002054423).
• BP6: Variant 6-15523157-T-C is Benign according to our data. Variant chr6-15523157-T-C is described in ClinVar as [Benign]. Clinvar id is 226620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTNBP1	NM_032122.5	c.874A>G	p.Arg292Gly	missense_variant	10/10	ENST00000344537.10	NP_115498.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTNBP1	ENST00000344537.10	c.874A>G	p.Arg292Gly	missense_variant	10/10	1	NM_032122.5	ENSP00000341680.6

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3662 AN: 152220 Hom.: 163 Cov.: 33

Gnomad AFR AF: 0.0830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00994

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00674 AC: 1696 AN: 251490 Hom.: 72 AF XY: 0.00483 AC XY: 656 AN XY: 135920

Gnomad AFR exome AF: 0.0860

Gnomad AMR exome AF: 0.00555

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00255 AC: 3731 AN: 1461890 Hom.: 132 Cov.: 31 AF XY: 0.00222 AC XY: 1616 AN XY: 727246

Gnomad4 AFR exome AF: 0.0842

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.00546

GnomAD4 genome AF: 0.0240 AC: 3662 AN: 152338 Hom.: 162 Cov.: 33 AF XY: 0.0239 AC XY: 1784 AN XY: 74494

Gnomad4 AFR AF: 0.0827

Gnomad4 AMR AF: 0.00993

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.00453 Hom.: 36

Bravo AF: 0.0271

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0908 AC: 400

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00829 AC: 1007

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Feb 04, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Arg292Gly in exon 10 of DTNBP1: This variant is not expected to have clinical si gnificance because it has been identified in 9.1% (400/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs73369534). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.28	T;.;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.69	T;T;T;T;T
MetaRNN	Benign	0.0021	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	M;.;.;.;.
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.7	D;D;.;.;D
REVEL	Benign	0.13
Sift	Benign	0.048	D;T;.;.;T
Sift4G	Benign	0.26	T;T;T;T;.
Polyphen		0.13	B;.;.;.;.
Vest4		0.22
MVP		0.055
MPC		0.22
ClinPred		0.021	T
GERP RS		2.4
Varity_R		0.12
gMVP		0.077

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

Publications

LitVar

Other links and lift over

dbSNP: rs73369534; hg19: chr6-15523388;