rs1555818396

Positions:

• chr19-40523602-G-A
• chr19-40523602-G-T

Variant summary

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

The NM_020971.3(SPTBN4):​c.3820G>A​(p.Glu1274Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTBN4 NM_020971.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22711569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN4	NM_020971.3	c.3820G>A	p.Glu1274Lys	missense_variant	17/36	ENST00000598249.6	NP_066022.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN4	ENST00000598249.6	c.3820G>A	p.Glu1274Lys	missense_variant	17/36	1	NM_020971.3	ENSP00000469242.1
SPTBN4	ENST00000352632.7	c.3820G>A	p.Glu1274Lys	missense_variant	17/36	5		ENSP00000263373.2
SPTBN4	ENST00000595535.5	c.3820G>A	p.Glu1274Lys	missense_variant	17/27	5		ENSP00000470693.1
SPTBN4	ENST00000597389.5	n.1996G>A		non_coding_transcript_exon_variant	4/24	5		ENSP00000472136.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	.;T;D;D;T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T;.;.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	.;.;L;L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	.;N;D;.;D
REVEL	Benign	0.14
Sift	Uncertain	0.027	.;D;D;.;D
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		0.32	.;.;B;B;.
Vest4		0.44
MutPred		0.47		Gain of MoRF binding (P = 7e-04);Gain of MoRF binding (P = 7e-04);Gain of MoRF binding (P = 7e-04);Gain of MoRF binding (P = 7e-04);Gain of MoRF binding (P = 7e-04);
MVP		0.54
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.36
gMVP		0.24

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: rs1555818396; hg19: chr19-41029509;