rs777273785

chr19-40570712-C-Achr19-40570712-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_020971.3(SPTBN4):c.7303C>A(p.Arg2435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R2435C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPTBN4 NM_020971.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

Genes affected

SPTBN4 (HGNC:14896): (spectrin beta, non-erythrocytic 4) Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein localizes to the nuclear matrix, PML nuclear bodies, and cytoplasmic vesicles. A highly similar gene in the mouse is required for localization of specific membrane proteins in polarized regions of neurons. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-40570712-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 559548.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15354326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN4	NM_020971.3	c.7303C>A	p.Arg2435Ser	missense_variant	33/36	ENST00000598249.6
SPTBN4	XM_017027049.2	c.7303C>A	p.Arg2435Ser	missense_variant	33/36
SPTBN4	XM_017027050.2	c.6961C>A	p.Arg2321Ser	missense_variant	31/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN4	ENST00000598249.6	c.7303C>A	p.Arg2435Ser	missense_variant	33/36	1	NM_020971.3	P1
SPTBN4	ENST00000352632.7	c.7303C>A	p.Arg2435Ser	missense_variant	33/36	5		P1
SPTBN4	ENST00000597389.5	c.*3459C>A		3_prime_UTR_variant, NMD_transcript_variant	21/24	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000872 AC: 2 AN: 229398 Hom.: 0 AF XY: 0.00000789 AC XY: 1 AN XY: 126782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456000 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724184

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000168 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.041	T;T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.27	N
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.65	D;D
PrimateAI	Uncertain	0.72	T
REVEL	Benign	0.22
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.68	.;P;P;.
Vest4		0.31
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.43
ClinPred		0.72	D
GERP RS		3.6
Varity_R		0.39
gMVP		0.46

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: rs777273785; hg19: chr19-41076618;