22-26483946-A-G

Position:

• chr22-26483946-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001013694.3(SRRD):​c.56A>G​(p.Lys19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,206,556 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: SRRD NM_001013694.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.818

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025335014).
• BP6: Variant 22-26483946-A-G is Benign according to our data. Variant chr22-26483946-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2303425.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRRD	NM_001013694.3	c.56A>G	p.Lys19Arg	missense_variant	1/7	ENST00000215917.11	NP_001013716.2
SRRD	XM_017028799.3	c.56A>G	p.Lys19Arg	missense_variant	1/6		XP_016884288.1
SRRD	XM_011530178.3	c.-204A>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.56A>G	p.Lys19Arg	missense_variant	1/7	1	NM_001013694.3	ENSP00000215917.6
HPS4	ENST00000699250.1	c.-613T>C		upstream_gene_variant				ENSP00000514237.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000166 AC: 2 AN: 1206556 Hom.: 0 Cov.: 33 AF XY: 0.00000170 AC XY: 1 AN XY: 587290

Gnomad4 AFR exome AF: 0.0000428

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.82
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.0	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.049
Sift	Benign	0.66	T
Sift4G	Benign	0.96	T
Polyphen		0.0	B
Vest4		0.080
MutPred		0.14		Loss of methylation at K19 (P = 0.0499);
MVP		0.076
MPC		0.023
ClinPred		0.058	T
GERP RS		-3.0
Varity_R		0.038
gMVP		0.25

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: chr22-26879912;