rs74907982

chr6-15523145-G-Achr6-15523145-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032122.5(DTNBP1):c.886C>T(p.Pro296Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,614,228 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (42 hom.)
• Consequence: DTNBP1 NM_032122.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.82

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=0.003545642).
• BP6: Variant 6-15523145-G-A is Benign according to our data. Variant chr6-15523145-G-A is described in ClinVar as [Benign]. Clinvar id is 262013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-15523145-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1867/152336) while in subpopulation AFR AF= 0.0415 (1725/41572). AF 95% confidence interval is 0.0399. There are 37 homozygotes in gnomad4. There are 886 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTNBP1	NM_032122.5	c.886C>T	p.Pro296Ser	missense_variant	10/10	ENST00000344537.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTNBP1	ENST00000344537.10	c.886C>T	p.Pro296Ser	missense_variant	10/10	1	NM_032122.5	P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1867 AN: 152218 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00316 AC: 794 AN: 251492 Hom.: 14 AF XY: 0.00235 AC XY: 320 AN XY: 135920

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00136 AC: 1990 AN: 1461892 Hom.: 42 Cov.: 31 AF XY: 0.00124 AC XY: 900 AN XY: 727246

Gnomad4 AFR exome AF: 0.0464

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.0123 AC: 1867 AN: 152336 Hom.: 37 Cov.: 33 AF XY: 0.0119 AC XY: 886 AN XY: 74504

Gnomad4 AFR AF: 0.0415

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00204 Hom.: 11

Bravo AF: 0.0150

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00372 AC: 452

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.9
Dann	Benign	0.60
DEOGEN2	Benign	0.059	T;.;T;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
MetaRNN	Benign	0.0035	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L;.;.;.;.
MutationTaster	Benign	0.77	D;D;D;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.39	N;N;.;.;N
REVEL	Benign	0.086
Sift	Benign	0.91	T;T;.;.;T
Sift4G	Benign	1.0	T;T;T;T;.
Polyphen		0.0090	B;.;.;.;.
Vest4		0.065
MVP		0.29
MPC		0.15
ClinPred		0.0083	T
GERP RS		4.5
Varity_R		0.022
gMVP		0.069

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: rs74907982; hg19: chr6-15523376;