22-26483951-C-G

Variant names:

• chr22-26483951-C-G
• rs910733217
• NM_001013694.3:c.61C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001013694.3(SRRD):​c.61C>G​(p.Arg21Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,211,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: SRRD NM_001013694.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.859
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• Hermansky-Pudlak syndrome with pulmonary fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14677984).

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.61C>G	p.Arg21Gly	missense	Exon 1 of 7	NP_001013716.2	Q9UH36
	HPS4	NM_022081.6	MANE Select	c.-756G>C		upstream_gene	N/A	NP_071364.4
	HPS4	NM_001349900.2		c.-756G>C		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.61C>G	p.Arg21Gly	missense	Exon 1 of 7	ENSP00000215917.6	Q9UH36
	SRRD	ENST00000942937.1		c.61C>G	p.Arg21Gly	missense	Exon 1 of 8	ENSP00000612996.1
	SRRD	ENST00000885114.1		c.61C>G	p.Arg21Gly	missense	Exon 1 of 7	ENSP00000555173.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000165 AC: 2 AN: 1211638 Hom.: 0 Cov.: 33 AF XY: 0.00000169 AC XY: 1 AN XY: 590382

African (AFR) AF: 0.0000426 AC: 1 AN: 23456

American (AMR) AF: 0.00 AC: 0 AN: 9406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16384

East Asian (EAS) AF: 0.00 AC: 0 AN: 27486

South Asian (SAS) AF: 0.0000194 AC: 1 AN: 51646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3408

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1001750

Other (OTH) AF: 0.00 AC: 0 AN: 49660

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.86
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.029
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.48	P
Vest4		0.28
MutPred		0.21		Loss of helix (P = 0.0068)
MVP		0.36
MPC		0.028
ClinPred		0.50	T
GERP RS		0.31
PromoterAI		0.18	Neutral
Varity_R		0.089
gMVP		0.56
Mutation Taster		=96/4	polymorphism

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: rs910733217; hg19: chr22-26879917;