rs66831137

Variant names:

• chr22-26483980-GGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGGGAGA-G
• rs66831137
• NM_001013694.3:c.108_149delGAGAGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGG

Your query was ambiguous. Multiple possible variants found:

• chr22-26483980-GGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGGGAGA-G
• chr22-26483980-GGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGGGAGA-GGAGGCGGCGCCCCGGGGGAGA
• chr22-26483980-GGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGGGAGA-GGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGGGAGA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.735
• Publications: 4 publications found

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]

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, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013694.3. 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
	SRRD	NM_001013694.3	MANE Select	c.108_149delGAGAGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGG	p.Arg37_Gly50del	disruptive_inframe_deletion	Exon 1 of 7	NP_001013716.2	Q9UH36
	HPS4	NM_022081.6	MANE Select	c.-827_-786delTCTCCCCCGGGGCGCCGCCTCTCTCCCCCGGGGCGCCGCCTC		upstream_gene	N/A	NP_071364.4
	HPS4	NM_001349900.2		c.-827_-786delTCTCCCCCGGGGCGCCGCCTCTCTCCCCCGGGGCGCCGCCTC		upstream_gene	N/A	NP_001336829.1	F1LLU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRRD	ENST00000215917.11	TSL:1 MANE Select	c.108_149delGAGAGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGG	p.Arg37_Gly50del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000215917.6	Q9UH36
	SRRD	ENST00000942937.1		c.108_149delGAGAGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGG	p.Arg37_Gly50del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000612996.1
	SRRD	ENST00000885114.1		c.108_149delGAGAGAGGCGGCGCCCCGGGGGAGAGAGGCGGCGCCCCGGGG	p.Arg37_Gly50del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000555173.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 65 AN: 145270 Hom.: 0 Cov.: 0

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: 22 AN: 9648 AF XY: 0.00204

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.: 4 AF XY: 0.000726 AC XY: 419 AN XY: 577024

African (AFR) AF: 0.000302 AC: 7 AN: 23212

American (AMR) AF: 0.000682 AC: 7 AN: 10260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16558

East Asian (EAS) AF: 0.000187 AC: 5 AN: 26796

South Asian (SAS) AF: 0.00117 AC: 61 AN: 51920

European-Finnish (FIN) AF: 0.000106 AC: 3 AN: 28244

Middle Eastern (MID) AF: 0.00150 AC: 5 AN: 3344

European-Non Finnish (NFE) AF: 0.000766 AC: 750 AN: 979508

Other (OTH) AF: 0.000557 AC: 27 AN: 48460

GnomAD4 genome AF: 0.000447 AC: 65 AN: 145376 Hom.: 0 Cov.: 0 AF XY: 0.000297 AC XY: 21 AN XY: 70610

African (AFR) AF: 0.000277 AC: 11 AN: 39740

American (AMR) AF: 0.000470 AC: 7 AN: 14898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 4644

South Asian (SAS) AF: 0.00 AC: 0 AN: 4486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000717 AC: 47 AN: 65542

Other (OTH) AF: 0.00 AC: 0 AN: 2010

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
Mutation Taster		=183/17	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs66831137; hg19: chr22-26879946;