Genetic Variant SPTBN5:p.Ser3625Cys (chr15-41850901-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_016642.4(SPTBN5):c.10874C>G(p.Ser3625Cys) 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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S3625S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPTBN5
NM_016642.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05

Variant links:

Genes affected

SPTBN5 (HGNC:15680): (spectrin beta, non-erythrocytic 5) Enables several functions, including cytoskeletal protein binding activity; dynein intermediate chain binding activity; and identical protein binding activity. Acts upstream of or within Golgi organization and lysosomal transport. Located in cytoplasm; photoreceptor connecting cilium; and photoreceptor disc membrane. [provided by Alliance of Genome Resources, Apr 2022]

SPTBN5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3980684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN5	NM_016642.4 link	c.10874C>G	p.Ser3625Cys	missense_variant	Exon 66 of 68	ENST00000320955.8	NP_057726.4	Q9NRC6
SPTBN5	XM_017022299.2 link	c.11054C>G	p.Ser3685Cys	missense_variant	Exon 64 of 66		XP_016877788.1
SPTBN5	XM_017022302.2 link	c.8231C>G	p.Ser2744Cys	missense_variant	Exon 52 of 54		XP_016877791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN5	ENST00000320955.8 link	c.10874C>G	p.Ser3625Cys	missense_variant	Exon 66 of 68	1	NM_016642.4	ENSP00000317790.6		Q9NRC6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451960

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721206

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10769C>G (p.S3590C) alteration is located in exon 66 (coding exon 65) of the SPTBN5 gene. This alteration results from a C to G substitution at nucleotide position 10769, causing the serine (S) at amino acid position 3590 to be replaced by a cysteine (C). 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

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.26

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.47

M_CAP

Benign

0.017

MetaRNN

Benign

0.40

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.094

Sift

Uncertain

0.023

Sift4G

Uncertain

0.032

Polyphen

0.99

Vest4

0.33

MutPred

0.56

Gain of catalytic residue at P3624 (P = 0.0111);

MVP

0.67

ClinPred

0.69

GERP RS

1.9

Varity_R

0.10

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over