chr22-26483919-A-G

Position:

• chr22-26483919-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001013694.3(SRRD):​c.29A>G​(p.Glu10Gly) 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: 1.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1034863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRRD	NM_001013694.3	c.29A>G	p.Glu10Gly	missense_variant	1/7	ENST00000215917.11	NP_001013716.2
SRRD	XM_017028799.3	c.29A>G	p.Glu10Gly	missense_variant	1/6		XP_016884288.1
SRRD	XM_011530178.3	c.-231A>G		5_prime_UTR_variant	1/7		XP_011528480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRRD	ENST00000215917.11	c.29A>G	p.Glu10Gly	missense_variant	1/7	1	NM_001013694.3	ENSP00000215917.6
HPS4	ENST00000699250.1	c.-586T>C		5_prime_UTR_variant	1/12			ENSP00000514237.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3472

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

Mar 18, 2024

The c.29A>G (p.E10G) alteration is located in exon 1 (coding exon 1) of the SRRD gene. This alteration results from a A to G substitution at nucleotide position 29, causing the glutamic acid (E) at amino acid position 10 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	0.097
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.069
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		0.0030	B
Vest4		0.15
MutPred		0.15		Gain of loop (P = 0.0121);
MVP		0.33
MPC		0.027
ClinPred		0.30	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.086
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs985066641; hg19: chr22-26879885;