chr22-26484006-C-T

Variant names:

• chr22-26484006-C-T
• rs1483024429
• NM_001013694.3:c.116C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001013694.3(SRRD):​c.116C>T​(p.Ala39Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,349,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SRRD NM_001013694.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.696
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059722036).

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.116C>T	p.Ala39Val	missense	Exon 1 of 7	NP_001013716.2	Q9UH36
	HPS4	NM_022081.6	MANE Select	c.-811G>A		upstream_gene	N/A	NP_071364.4
	HPS4	NM_001349900.2		c.-811G>A		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.116C>T	p.Ala39Val	missense	Exon 1 of 7	ENSP00000215917.6	Q9UH36
	SRRD	ENST00000942937.1		c.116C>T	p.Ala39Val	missense	Exon 1 of 8	ENSP00000612996.1
	SRRD	ENST00000885114.1		c.116C>T	p.Ala39Val	missense	Exon 1 of 7	ENSP00000555173.1

Frequencies

GnomAD3 genomes AF: 0.0000273 AC: 4 AN: 146440 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000609

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 124 AN: 1203532 Hom.: 0 Cov.: 45 AF XY: 0.0000974 AC XY: 57 AN XY: 585466

African (AFR) AF: 0.00 AC: 0 AN: 23834

American (AMR) AF: 0.00 AC: 0 AN: 12344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17686

East Asian (EAS) AF: 0.00 AC: 0 AN: 26910

South Asian (SAS) AF: 0.00 AC: 0 AN: 53298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28300

Middle Eastern (MID) AF: 0.000289 AC: 1 AN: 3466

European-Non Finnish (NFE) AF: 0.000123 AC: 122 AN: 988518

Other (OTH) AF: 0.0000203 AC: 1 AN: 49176

GnomAD4 genome AF: 0.0000273 AC: 4 AN: 146440 Hom.: 0 Cov.: 26 AF XY: 0.0000421 AC XY: 3 AN XY: 71328

African (AFR) AF: 0.00 AC: 0 AN: 40210

American (AMR) AF: 0.00 AC: 0 AN: 14868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 4766

South Asian (SAS) AF: 0.00 AC: 0 AN: 4348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000609 AC: 4 AN: 65646

Other (OTH) AF: 0.00 AC: 0 AN: 2010

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.70
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.0010
Sift	Benign	0.16	T
Sift4G	Benign	0.28	T
Vest4		0.083
MutPred		0.25		Gain of MoRF binding (P = 0.0826)
MVP		0.28
MPC		0.025
ClinPred		0.10	T
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.066
gMVP		0.19
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1483024429; hg19: chr22-26879972;