Genetic Variant SPTBN5:p.Leu3636Val (chr15-41850869-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016642.4(SPTBN5):c.10906C>G(p.Leu3636Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,447,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

SPTBN5
NM_016642.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.987

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08475277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN5	NM_016642.4 link	c.10906C>G	p.Leu3636Val	missense_variant	Exon 66 of 68	ENST00000320955.8	NP_057726.4	Q9NRC6
SPTBN5	XM_017022299.2 link	c.11086C>G	p.Leu3696Val	missense_variant	Exon 64 of 66		XP_016877788.1
SPTBN5	XM_017022302.2 link	c.8263C>G	p.Leu2755Val	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.10906C>G	p.Leu3636Val	missense_variant	Exon 66 of 68	1	NM_016642.4	ENSP00000317790.6		Q9NRC6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1447634

Hom.:

Cov.:

AF XY:

0.00000557

AC XY:

AN XY:

718678

show subpopulations

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:

0.0000360

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.0000167

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

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10801C>G (p.L3601V) 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 10801, causing the leucine (L) at amino acid position 3601 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

0.098

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.9

DANN

Benign

0.96

DEOGEN2

Benign

0.0097

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.34

M_CAP

Benign

0.0025

MetaRNN

Benign

0.085

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.91

REVEL

Benign

0.0090

Sift

Benign

0.047

Sift4G

Uncertain

0.024

Polyphen

0.079

Vest4

0.32

MutPred

0.44

Gain of MoRF binding (P = 0.0916);

MVP

0.25

ClinPred

0.10

GERP RS

1.9

Varity_R

0.054

gMVP

0.085

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