19-40472709-C-G

Variant names:

• chr19-40472709-C-G
• NM_020971.3:c.88C>G

Variant summary

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

The NM_020971.3(SPTBN4):​c.88C>G​(p.Arg30Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPTBN4 NM_020971.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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=0.22269404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN4	NM_020971.3	c.88C>G	p.Arg30Gly	missense_variant	Exon 2 of 36	ENST00000598249.6	NP_066022.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN4	ENST00000598249.6	c.88C>G	p.Arg30Gly	missense_variant	Exon 2 of 36	1	NM_020971.3	ENSP00000469242.1
SPTBN4	ENST00000352632.7	c.88C>G	p.Arg30Gly	missense_variant	Exon 2 of 36	5		ENSP00000263373.2
SPTBN4	ENST00000595535.5	c.88C>G	p.Arg30Gly	missense_variant	Exon 2 of 27	5		ENSP00000470693.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460082 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726202

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88C>G (p.R30G) alteration is located in exon 2 (coding exon 1) of the SPTBN4 gene. This alteration results from a C to G substitution at nucleotide position 88, causing the arginine (R) at amino acid position 30 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	Benign	0.092
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0060	.;T;T;T;T
Eigen	Benign	-0.099
Eigen_PC	Benign	0.077
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.62	T;.;.;T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.90	.;.;L;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.46	.;.;N;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.51	.;.;T;.;T
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.99	.;.;D;D;.
Vest4		0.53
MutPred		0.22		Loss of stability (P = 0.0652);Loss of stability (P = 0.0652);Loss of stability (P = 0.0652);Loss of stability (P = 0.0652);Loss of stability (P = 0.0652);
MVP		0.72
ClinPred		0.64	D
GERP RS		5.1
Varity_R		0.19
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-40978616;