15-41851326-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016642.4(SPTBN5):c.10700G>A(p.Gly3567Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,398,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: SPTBN5 NM_016642.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.253

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]

ACMG classification

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=0.08927366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN5	NM_016642.4	c.10700G>A	p.Gly3567Asp	missense_variant	64/68	ENST00000320955.8
SPTBN5	XM_017022299.2	c.10880G>A	p.Gly3627Asp	missense_variant	62/66
SPTBN5	XM_017022302.2	c.8057G>A	p.Gly2686Asp	missense_variant	50/54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN5	ENST00000320955.8	c.10700G>A	p.Gly3567Asp	missense_variant	64/68	1	NM_016642.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000194 AC: 3 AN: 154512 Hom.: 0 AF XY: 0.0000244 AC XY: 2 AN XY: 81800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000275

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000500 AC: 7 AN: 1398948 Hom.: 0 Cov.: 35 AF XY: 0.00000435 AC XY: 3 AN XY: 689990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000168

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The c.10595G>A (p.G3532D) alteration is located in exon 64 (coding exon 63) of the SPTBN5 gene. This alteration results from a G to A substitution at nucleotide position 10595, causing the glycine (G) at amino acid position 3532 to be replaced by an aspartic acid (D). 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	0.092
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	4.9
Dann	Benign	0.75
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.026
Sift	Benign	0.21	T
Sift4G	Benign	0.10	T
Polyphen		0.0080	B
Vest4		0.11
MutPred		0.43		Loss of catalytic residue at S3569 (P = 0.0404);
MVP		0.43
ClinPred		0.24	T
GERP RS		1.5
Varity_R		0.075
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs1461285965; hg19: chr15-42143524; COSMIC: COSV58020088; COSMIC: COSV58020088;