22-26484046-G-T

Variant names:

• chr22-26484046-G-T
• rs1201317936
• NM_001013694.3:c.156G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001013694.3(SRRD):​c.156G>T​(p.Glu52Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000813 in 1,229,684 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E52K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: SRRD NM_001013694.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.440
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06243983).

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.156G>T	p.Glu52Asp	missense	Exon 1 of 7	NP_001013716.2	Q9UH36
	HPS4	NM_001349901.1		c.-760C>A		upstream_gene	N/A	NP_001336830.1	F1LLU8
	HPS4	NM_001349896.1		c.-760C>A		upstream_gene	N/A	NP_001336825.1	Q9NQG7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRRD	ENST00000215917.11	TSL:1 MANE Select	c.156G>T	p.Glu52Asp	missense	Exon 1 of 7	ENSP00000215917.6	Q9UH36
	SRRD	ENST00000942937.1		c.156G>T	p.Glu52Asp	missense	Exon 1 of 8	ENSP00000612996.1
	SRRD	ENST00000885114.1		c.156G>T	p.Glu52Asp	missense	Exon 1 of 7	ENSP00000555173.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.13e-7 AC: 1 AN: 1229684 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 606628

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24578

American (AMR) AF: 0.00 AC: 0 AN: 24158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19564

East Asian (EAS) AF: 0.00 AC: 0 AN: 22050

South Asian (SAS) AF: 0.00 AC: 0 AN: 71570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3830

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 992138

Other (OTH) AF: 0.00 AC: 0 AN: 48302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.77
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.44
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.077
Sift	Benign	0.35	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.14		Gain of loop (P = 0.069)
MVP		0.26
MPC		0.024
ClinPred		0.096	T
GERP RS		-0.78
PromoterAI		0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.18
Mutation Taster		=100/0	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: rs1201317936; hg19: chr22-26880012;