Genetic Variant SRRD:p.Ala40Gly (chr22-26484009-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001013694.3(SRRD):c.119C>G(p.Ala40Gly) 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SRRD
NM_001013694.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.696

Publications

0 publications found

Variant links:

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]

SRRD links:

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

HPS4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.06527886).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SRRD	NM_001013694.3	MANE Select	c.119C>G	p.Ala40Gly	missense	Exon 1 of 7	NP_001013716.2	Q9UH36
HPS4	NM_022081.6	MANE Select	c.-814G>C		upstream_gene	N/A	NP_071364.4
HPS4	NM_001349900.2		c.-814G>C		upstream_gene	N/A	NP_001336829.1	F1LLU8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SRRD	ENST00000215917.11	TSL:1 MANE Select	c.119C>G	p.Ala40Gly	missense	Exon 1 of 7	ENSP00000215917.6	Q9UH36
SRRD	ENST00000942937.1		c.119C>G	p.Ala40Gly	missense	Exon 1 of 8	ENSP00000612996.1
SRRD	ENST00000885114.1		c.119C>G	p.Ala40Gly	missense	Exon 1 of 7	ENSP00000555173.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1194492

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

581424

African (AFR)

AF:

0.00

AC:

AN:

23560

American (AMR)

AF:

0.00

AC:

AN:

12120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17422

East Asian (EAS)

AF:

0.00

AC:

AN:

26092

South Asian (SAS)

AF:

0.00

AC:

AN:

53538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3376

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

982676

Other (OTH)

AF:

0.00

AC:

AN:

48392

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.013

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00081

LIST_S2

Benign

0.24

M_CAP

Benign

0.0029

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.70

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.67

REVEL

Benign

0.0060

Sift

Benign

0.31

Sift4G

Benign

0.39

Vest4

0.099

MutPred

0.24

Loss of stability (P = 0.017)

MVP

0.15

MPC

0.025

ClinPred

0.11

PromoterAI

-0.15

Neutral

(source)

Varity_R

0.096

gMVP

0.16

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over