NM_032122.5:c.*151_*152dupAA

Variant names:

• chr6-15522822-C-CTT
• rs555440397
• NM_032122.5:c.*151_*152dupAA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_032122.5(DTNBP1):​c.*151_*152dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000859 in 1,375,388 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (1 hom.)
• Consequence: DTNBP1 NM_032122.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000895 (1095/1223002) while in subpopulation NFE AF = 0.00112 (1031/919442). AF 95% confidence interval is 0.00106. There are 1 homozygotes in GnomAdExome4. There are 549 alleles in the male GnomAdExome4 subpopulation. Median coverage is 16. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*151_*152dupAA		3_prime_UTR	Exon 10 of 10	NP_115498.2
	DTNBP1	NM_001271668.2		c.*151_*152dupAA		3_prime_UTR	Exon 9 of 9	NP_001258597.1	A6NFV8
	DTNBP1	NM_001271669.2		c.*151_*152dupAA		3_prime_UTR	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.*151_*152dupAA		3_prime_UTR	Exon 10 of 10	ENSP00000341680.6	Q96EV8-1
	DTNBP1	ENST00000622898.4	TSL:1	c.*151_*152dupAA		3_prime_UTR	Exon 8 of 8	ENSP00000481997.1	A0A087WYP9
	DTNBP1	ENST00000857317.1		c.*151_*152dupAA		3_prime_UTR	Exon 10 of 10	ENSP00000527376.1

Frequencies

GnomAD3 genomes AF: 0.000571 AC: 87 AN: 152268 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000895 AC: 1095 AN: 1223002 Hom.: 1 Cov.: 16 AF XY: 0.000891 AC XY: 549 AN XY: 616064

African (AFR) AF: 0.000210 AC: 6 AN: 28546

American (AMR) AF: 0.000511 AC: 21 AN: 41108

Ashkenazi Jewish (ASJ) AF: 0.0000437 AC: 1 AN: 22886

East Asian (EAS) AF: 0.00 AC: 0 AN: 38216

South Asian (SAS) AF: 0.00 AC: 0 AN: 75876

European-Finnish (FIN) AF: 0.000147 AC: 6 AN: 40874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3646

European-Non Finnish (NFE) AF: 0.00112 AC: 1031 AN: 919442

Other (OTH) AF: 0.000572 AC: 30 AN: 52408

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152386 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74518

African (AFR) AF: 0.000120 AC: 5 AN: 41594

American (AMR) AF: 0.00111 AC: 17 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000955 AC: 65 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000432 Hom.: 0

Bravo AF: 0.000703

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hermansky-Pudlak syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs555440397; hg19: chr6-15523053;