NM_032122.5:c.355+21G>C

Variant names:

• chr6-15627322-C-G
• rs16876738
• NM_032122.5:c.355+21G>C

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.355+21G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,610,846 control chromosomes in the GnomAD database, including 21,393 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1866 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19527 hom.)
• Consequence: DTNBP1 NM_032122.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0400
• Publications: 10 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), ClinGen, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-15627322-C-G is Benign according to our data. Variant chr6-15627322-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.289 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	NM_032122.5	MANE Select	c.355+21G>C		intron	N/A	NP_115498.2
	DTNBP1	NM_001271668.2		c.304+21G>C		intron	N/A	NP_001258597.1
	DTNBP1	NM_001271669.2		c.250+21G>C		intron	N/A	NP_001258598.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	ENST00000344537.10	TSL:1 MANE Select	c.355+21G>C		intron	N/A	ENSP00000341680.6
	DTNBP1	ENST00000622898.4	TSL:1	c.250+21G>C		intron	N/A	ENSP00000481997.1
	DTNBP1	ENST00000338950.9	TSL:1	c.355+21G>C		intron	N/A	ENSP00000344718.5

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22461 AN: 152010 Hom.: 1866 Cov.: 32

Gnomad AFR AF: 0.0865

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.170 AC: 42417 AN: 249564 AF XY: 0.172

Gnomad AFR exome AF: 0.0875

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.302

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.159 AC: 231800 AN: 1458718 Hom.: 19527 Cov.: 32 AF XY: 0.161 AC XY: 116865 AN XY: 725828

African (AFR) AF: 0.0881 AC: 2944 AN: 33406

American (AMR) AF: 0.166 AC: 7424 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7131 AN: 26088

East Asian (EAS) AF: 0.272 AC: 10785 AN: 39598

South Asian (SAS) AF: 0.172 AC: 14817 AN: 86120

European-Finnish (FIN) AF: 0.141 AC: 7363 AN: 52052

Middle Eastern (MID) AF: 0.281 AC: 1601 AN: 5698

European-Non Finnish (NFE) AF: 0.152 AC: 169138 AN: 1110830

Other (OTH) AF: 0.176 AC: 10597 AN: 60262

GnomAD4 genome AF: 0.148 AC: 22474 AN: 152128 Hom.: 1866 Cov.: 32 AF XY: 0.150 AC XY: 11182 AN XY: 74342

African (AFR) AF: 0.0864 AC: 3588 AN: 41508

American (AMR) AF: 0.172 AC: 2620 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 948 AN: 3468

East Asian (EAS) AF: 0.301 AC: 1557 AN: 5168

South Asian (SAS) AF: 0.183 AC: 882 AN: 4818

European-Finnish (FIN) AF: 0.148 AC: 1566 AN: 10590

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10746 AN: 67982

Other (OTH) AF: 0.190 AC: 403 AN: 2116

Alfa AF: 0.126 Hom.: 328

Bravo AF: 0.146

Asia WGS AF: 0.225 AC: 784 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.34
PhyloP100		0.040
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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

Other links and lift over

dbSNP: rs16876738; hg19: chr6-15627553; COSMIC: COSV59038663;