Genetic Variant NM_001013694.3:c.129_149dupGAGAGAGGCGGCGCCCCGGGG (chr22-26483980-G-GGAGGCGGCGCCCCGGGGGAGA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001013694.3(SRRD):c.129_149dupGAGAGAGGCGGCGCCCCGGGG(p.Gly50_Pro51insArgGluAlaAlaProArgGly) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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. Synonymous variant affecting the same amino acid position (i.e. G50G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

SRRD
NM_001013694.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.467

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: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001013694.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRRD	NM_001013694.3 link	c.129_149dupGAGAGAGGCGGCGCCCCGGGG	p.Gly50_Pro51insArgGluAlaAlaProArgGly	disruptive_inframe_insertion	Exon 1 of 7	ENST00000215917.11	NP_001013716.2	Q9UH36
HPS4	NM_022081.6 link	c.-806_-786dupTCTCCCCCGGGGCGCCGCCTC		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.129_149dupGAGAGAGGCGGCGCCCCGGGG	p.Gly50_Pro51insArgGluAlaAlaProArgGly	disruptive_inframe_insertion	Exon 1 of 7	1	NM_001013694.3	ENSP00000215917.6		Q9UH36
HPS4	ENST00000398145.7 link	c.-806_-786dupTCTCCCCCGGGGCGCCGCCTC		upstream_gene_variant		1	NM_022081.6	ENSP00000381213.2		Q9NQG7-1

Frequencies

GnomAD3 genomes

AF:

0.000551

AC:

AN:

145272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000202

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00178

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000305

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000673

AC:

AN:

1188326

Hom.:

Cov.:

AF XY:

0.0000676

AC XY:

AN XY:

577030

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

23212

American (AMR)

AF:

0.0000974

AC:

AN:

10262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16558

East Asian (EAS)

AF:

0.00

AC:

AN:

26796

South Asian (SAS)

AF:

0.000327

AC:

AN:

51922

European-Finnish (FIN)

AF:

0.0000354

AC:

AN:

28244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3344

European-Non Finnish (NFE)

AF:

0.0000245

AC:

AN:

979530

Other (OTH)

AF:

0.000165

AC:

AN:

48458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000550

AC:

AN:

145378

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

70612

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

39740

American (AMR)

AF:

0.000201

AC:

AN:

14900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3388

East Asian (EAS)

AF:

0.00

AC:

AN:

4644

South Asian (SAS)

AF:

0.00156

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:

0.0000305

AC:

AN:

65542

Other (OTH)

AF:

0.00

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

-0.47

Mutation Taster

=79/21

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