dbSNP rs66831137: SRRD:p.Arg37_Gly50del (chr22-26483980-GGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGGGAGA-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4BS2

The NM_001013694.3(SRRD):c.108_149delGAGAGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGG(p.Arg37_Gly50del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,333,678 control chromosomes in the GnomAD database, including 4 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00073 ( 4 hom. )

Consequence

SRRD
NM_001013694.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.735

Publications

4 publications found

Variant links:

Genes affected

SRRD (HGNC:33910): (SRR1 domain containing) Predicted to be involved in microtubule-based process; regulation of circadian rhythm; and regulation of heme biosynthetic process. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SRRD links:

HPS4 (HGNC:15844): (HPS4 biogenesis of lysosomal organelles complex 3 subunit 2) This gene encodes a protein component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

HPS4 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
Hermansky-Pudlak syndrome with pulmonary fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HPS4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001013694.3.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRRD	NM_001013694.3 link	c.108_149delGAGAGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGG	p.Arg37_Gly50del	disruptive_inframe_deletion	Exon 1 of 7	ENST00000215917.11	NP_001013716.2	Q9UH36
HPS4	NM_022081.6 link	c.-827_-786delTCTCCCCCGGGGCGCCGCCTCTCTCCCCCGGGGCGCCGCCTC		upstream_gene_variant		ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRRD	ENST00000215917.11 link	c.108_149delGAGAGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGG	p.Arg37_Gly50del	disruptive_inframe_deletion	Exon 1 of 7	1	NM_001013694.3	ENSP00000215917.6		Q9UH36
HPS4	ENST00000398145.7 link	c.-827_-786delTCTCCCCCGGGGCGCCGCCTCTCTCCCCCGGGGCGCCGCCTC		upstream_gene_variant		1	NM_022081.6	ENSP00000381213.2		Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

145270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000278

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000471

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:

0.000717

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00228

AC:

AN:

9648

AF XY:

0.00204

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000727

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00306

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000728

AC:

865

AN:

1188302

Hom.:

AF XY:

0.000726

AC XY:

419

AN XY:

577024

show subpopulations

African (AFR)

AF:

0.000302

AC:

AN:

23212

American (AMR)

AF:

0.000682

AC:

AN:

10260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16558

East Asian (EAS)

AF:

0.000187

AC:

AN:

26796

South Asian (SAS)

AF:

0.00117

AC:

AN:

51920

European-Finnish (FIN)

AF:

0.000106

AC:

AN:

28244

Middle Eastern (MID)

AF:

0.00150

AC:

AN:

3344

European-Non Finnish (NFE)

AF:

0.000766

AC:

750

AN:

979508

Other (OTH)

AF:

0.000557

AC:

AN:

48460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.615

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000447

AC:

AN:

145376

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

AN XY:

70610

show subpopulations

African (AFR)

AF:

0.000277

AC:

AN:

39740

American (AMR)

AF:

0.000470

AC:

AN:

14898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3388

East Asian (EAS)

AF:

0.00

AC:

AN:

4644

South Asian (SAS)

AF:

0.00

AC:

AN:

4486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000717

AC:

AN:

65542

Other (OTH)

AF:

0.00

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.73

Mutation Taster

=183/17

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over