19-40570712-C-G

Variant names:

• chr19-40570712-C-G
• NM_020971.3:c.7303C>G

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>G​(p.Arg2435Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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)
• Consequence: SPTBN4 NM_020971.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.17023891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN4	NM_020971.3	c.7303C>G	p.Arg2435Gly	missense_variant	Exon 33 of 36	ENST00000598249.6	NP_066022.2
SPTBN4	XM_017027049.2	c.7303C>G	p.Arg2435Gly	missense_variant	Exon 33 of 36		XP_016882538.1
SPTBN4	XM_017027050.2	c.6961C>G	p.Arg2321Gly	missense_variant	Exon 31 of 34		XP_016882539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN4	ENST00000598249.6	c.7303C>G	p.Arg2435Gly	missense_variant	Exon 33 of 36	1	NM_020971.3	ENSP00000469242.1
SPTBN4	ENST00000352632.7	c.7303C>G	p.Arg2435Gly	missense_variant	Exon 33 of 36	5		ENSP00000263373.2
SPTBN4	ENST00000597389.5	n.*3459C>G		non_coding_transcript_exon_variant	Exon 21 of 24	5		ENSP00000472136.1
SPTBN4	ENST00000597389.5	n.*3459C>G		3_prime_UTR_variant	Exon 21 of 24	5		ENSP00000472136.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7303C>G (p.R2435G) alteration is located in exon 33 (coding exon 32) of the SPTBN4 gene. This alteration results from a C to G substitution at nucleotide position 7303, causing the arginine (R) at amino acid position 2435 to be replaced by a glycine (G). 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	Pathogenic	0.58
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;D;D;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.78	.;.;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.035	.;N;N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.1	.;D;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.0010	.;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.0070	.;B;B;.
Vest4		0.44
MutPred		0.48		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		0.36
ClinPred		0.92	D
GERP RS		3.6
Varity_R		0.44
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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.

Other links and lift over

hg19: chr19-41076618;