rs17470454

Variant names:

• chr6-15523217-G-A
• rs17470454
• NM_032122.5:c.814C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032122.5(DTNBP1):​c.814C>T​(p.Pro272Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.049 in 1,613,910 control chromosomes in the GnomAD database, including 2,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (201 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2272 hom.)
• Consequence: DTNBP1 NM_032122.5 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.17
• Publications: 23 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016671717).
• BP6: Variant 6-15523217-G-A is Benign according to our data. Variant chr6-15523217-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032122.5. 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
	DTNBP1	NM_032122.5	MANE Select	c.814C>T	p.Pro272Ser	missense splice_region	Exon 10 of 10	NP_115498.2
	DTNBP1	NM_001271668.2		c.763C>T	p.Pro255Ser	missense splice_region	Exon 9 of 9	NP_001258597.1	A6NFV8
	DTNBP1	NM_001271669.2		c.709C>T	p.Pro237Ser	missense splice_region	Exon 8 of 8	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.814C>T	p.Pro272Ser	missense splice_region	Exon 10 of 10	ENSP00000341680.6	Q96EV8-1
	DTNBP1	ENST00000622898.4	TSL:1	c.709C>T	p.Pro237Ser	missense splice_region	Exon 8 of 8	ENSP00000481997.1	A0A087WYP9
	DTNBP1	ENST00000857317.1		c.895C>T	p.Pro299Ser	missense splice_region	Exon 10 of 10	ENSP00000527376.1

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6328 AN: 152210 Hom.: 201 Cov.: 33

Gnomad AFR AF: 0.00946

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0259

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0579

Gnomad OTH AF: 0.0358

GnomAD2 exomes AF: 0.0425 AC: 10675 AN: 251402 AF XY: 0.0423

Gnomad AFR exome AF: 0.00815

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.0593

Gnomad OTH exome AF: 0.0422

GnomAD4 exome AF: 0.0498 AC: 72806 AN: 1461582 Hom.: 2272 Cov.: 31 AF XY: 0.0486 AC XY: 35302 AN XY: 727112

African (AFR) AF: 0.00777 AC: 260 AN: 33478

American (AMR) AF: 0.0167 AC: 747 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 372 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00486 AC: 419 AN: 86196

European-Finnish (FIN) AF: 0.124 AC: 6597 AN: 53412

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5766

European-Non Finnish (NFE) AF: 0.0557 AC: 61917 AN: 1111784

Other (OTH) AF: 0.0405 AC: 2447 AN: 60386

GnomAD4 genome AF: 0.0415 AC: 6328 AN: 152328 Hom.: 201 Cov.: 33 AF XY: 0.0429 AC XY: 3198 AN XY: 74502

African (AFR) AF: 0.00943 AC: 392 AN: 41560

American (AMR) AF: 0.0258 AC: 395 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.130 AC: 1376 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0579 AC: 3937 AN: 68032

Other (OTH) AF: 0.0354 AC: 75 AN: 2116

Alfa AF: 0.0449 Hom.: 552

Bravo AF: 0.0315

TwinsUK AF: 0.0556 AC: 206

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.00976 AC: 43

ESP6500EA AF: 0.0508 AC: 437

ExAC AF: 0.0435 AC: 5281

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0469

EpiControl AF: 0.0448

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.14	B
Vest4		0.099
MPC		0.13
ClinPred		0.019	T
GERP RS		3.6
Varity_R		0.034
gMVP		0.23
Mutation Taster		=94/6	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

Other links and lift over

dbSNP: rs17470454; hg19: chr6-15523448; COSMIC: COSV59044435; COSMIC: COSV59044435;