15-41849902-G-A

Variant names:

• chr15-41849902-G-A
• rs55807335
• NM_016642.4:c.10979C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_016642.4(SPTBN5):​c.10979C>T​(p.Thr3660Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000941 in 1,593,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (0 hom.)
• Consequence: SPTBN5 NM_016642.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.806

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0062273443).
• BP6: Variant 15-41849902-G-A is Benign according to our data. Variant chr15-41849902-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2645200.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN5	NM_016642.4	c.10979C>T	p.Thr3660Met	missense_variant	Exon 67 of 68	ENST00000320955.8	NP_057726.4
SPTBN5	XM_017022299.2	c.11159C>T	p.Thr3720Met	missense_variant	Exon 65 of 66		XP_016877788.1
SPTBN5	XM_017022302.2	c.8336C>T	p.Thr2779Met	missense_variant	Exon 53 of 54		XP_016877791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN5	ENST00000320955.8	c.10979C>T	p.Thr3660Met	missense_variant	Exon 67 of 68	1	NM_016642.4	ENSP00000317790.6
SPTBN5	ENST00000563899.1	n.671C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000713 AC: 154 AN: 216064 Hom.: 0 AF XY: 0.000771 AC XY: 90 AN XY: 116758

Gnomad AFR exome AF: 0.000484

Gnomad AMR exome AF: 0.000901

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000526

Gnomad FIN exome AF: 0.0000524

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000729

GnomAD4 exome AF: 0.000949 AC: 1367 AN: 1440954 Hom.: 0 Cov.: 30 AF XY: 0.000994 AC XY: 710 AN XY: 714564

Gnomad4 AFR exome AF: 0.000302

Gnomad4 AMR exome AF: 0.000912

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000266

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000620

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000966 AC XY: 72 AN XY: 74506

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000907

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000727 AC: 6

ExAC AF: 0.000557 AC: 67

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10874C>T (p.T3625M) alteration is located in exon 67 (coding exon 66) of the SPTBN5 gene. This alteration results from a C to T substitution at nucleotide position 10874, causing the threonine (T) at amino acid position 3625 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPTBN5: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.4
DANN	Benign	0.89
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.073
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.012	D
Polyphen		0.078	B
Vest4		0.22
MVP		0.53
ClinPred		0.0081	T
GERP RS		0.29
Varity_R		0.014
gMVP		0.14

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: rs55807335; hg19: chr15-42142100;