22-26484009-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001013694.3(SRRD):​c.119C>T​(p.Ala40Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,340,756 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00012 (3 hom.)
• Consequence: SRRD NM_001013694.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.696

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013597041).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRRD	NM_001013694.3	c.119C>T	p.Ala40Val	missense_variant	Exon 1 of 7	ENST00000215917.11	NP_001013716.2
HPS4	NM_022081.6	c.-814G>A		upstream_gene_variant		ENST00000398145.7	NP_071364.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRRD	ENST00000215917.11	c.119C>T	p.Ala40Val	missense_variant	Exon 1 of 7	1	NM_001013694.3	ENSP00000215917.6
HPS4	ENST00000398145.7	c.-814G>A		upstream_gene_variant		1	NM_022081.6	ENSP00000381213.2

Frequencies

GnomAD3 genomes AF: 0.000575 AC: 84 AN: 146132 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000605

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00161

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000305

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000269 AC: 6 AN: 22326 Hom.: 0 AF XY: 0.000296 AC XY: 4 AN XY: 13512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.000117 AC: 140 AN: 1194488 Hom.: 3 Cov.: 45 AF XY: 0.000151 AC XY: 88 AN XY: 581424

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.000660

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000383

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000611

Gnomad4 OTH exome AF: 0.000351

GnomAD4 genome AF: 0.000574 AC: 84 AN: 146268 Hom.: 0 Cov.: 26 AF XY: 0.000547 AC XY: 39 AN XY: 71322

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.000604

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00161

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000305

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000990 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119C>T (p.A40V) alteration is located in exon 1 (coding exon 1) of the SRRD gene. This alteration results from a C to T substitution at nucleotide position 119, causing the alanine (A) at amino acid position 40 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.0020
Sift	Benign	0.23	T
Sift4G	Benign	0.54	T
Vest4		0.12
MutPred		0.24		Loss of helix (P = 0.079);
MVP		0.19
MPC		0.025
ClinPred		0.063	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.069
gMVP		0.18

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: rs780208454; hg19: chr22-26879975;