22-26483972-C-G

Position:

• chr22-26483972-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001013694.3(SRRD):​c.82C>G​(p.Arg28Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SRRD NM_001013694.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.218

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06541067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRRD	NM_001013694.3	c.82C>G	p.Arg28Gly	missense_variant	1/7	ENST00000215917.11
SRRD	XM_017028799.3	c.82C>G	p.Arg28Gly	missense_variant	1/6
SRRD	XM_011530178.3	c.-178C>G		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRRD	ENST00000215917.11	c.82C>G	p.Arg28Gly	missense_variant	1/7	1	NM_001013694.3	P1
HPS4	ENST00000699250.1			upstream_gene_variant				A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.82C>G (p.R28G) alteration is located in exon 1 (coding exon 1) of the SRRD gene. This alteration results from a C to G substitution at nucleotide position 82, causing the arginine (R) at amino acid position 28 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.019
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.035	D
Polyphen		0.0060	B
Vest4		0.16
MutPred		0.26		Loss of methylation at R28 (P = 0.0106);
MVP		0.25
MPC		0.028
ClinPred		0.65	D
GERP RS		-1.3
Varity_R		0.13
gMVP		0.41

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-26879938;