rs780208454

Variant names:

• chr22-26484009-C-A
• rs780208454
• NM_001013694.3:c.119C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-26484009-C-A
• chr22-26484009-C-G
• chr22-26484009-C-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.119C>A​(p.Ala40Glu) 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. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A40V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 26)
• Consequence: SRRD NM_001013694.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056174725).

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.119C>A	p.Ala40Glu	missense	Exon 1 of 7	NP_001013716.2	Q9UH36
	HPS4	NM_022081.6	MANE Select	c.-814G>T		upstream_gene	N/A	NP_071364.4
	HPS4	NM_001349900.2		c.-814G>T		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.119C>A	p.Ala40Glu	missense	Exon 1 of 7	ENSP00000215917.6	Q9UH36
	SRRD	ENST00000942937.1		c.119C>A	p.Ala40Glu	missense	Exon 1 of 8	ENSP00000612996.1
	SRRD	ENST00000885114.1		c.119C>A	p.Ala40Glu	missense	Exon 1 of 7	ENSP00000555173.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 26

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.4
DANN	Benign	0.37
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.70
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.027
Sift	Benign	0.87	T
Sift4G	Benign	0.36	T
Vest4		0.16
MutPred		0.25		Loss of MoRF binding (P = 0.0345)
MVP		0.14
MPC		0.026
ClinPred		0.066	T
PromoterAI		-0.086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.089
gMVP		0.19
Mutation Taster		=99/1	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: rs780208454; hg19: chr22-26879975;