19-40472709-C-T

Variant names:

• chr19-40472709-C-T
• rs770792509
• NM_020971.3:c.88C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020971.3(SPTBN4):​c.88C>T​(p.Arg30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: SPTBN4 NM_020971.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61
• Publications: 4 publications found

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]

SPTBN4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia, neuropathy, and deafness

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Illumina, ClinGen

ENSG00000298987 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16769865).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020971.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN4	NM_020971.3	MANE Select	c.88C>T	p.Arg30Trp	missense	Exon 2 of 36	NP_066022.2	Q9H254-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN4	ENST00000598249.6	TSL:1 MANE Select	c.88C>T	p.Arg30Trp	missense	Exon 2 of 36	ENSP00000469242.1	Q9H254-1
	SPTBN4	ENST00000352632.7	TSL:5	c.88C>T	p.Arg30Trp	missense	Exon 2 of 36	ENSP00000263373.2	Q9H254-1
	SPTBN4	ENST00000595535.5	TSL:5	c.88C>T	p.Arg30Trp	missense	Exon 2 of 27	ENSP00000470693.1	M0QZQ3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000814 AC: 2 AN: 245722 AF XY: 0.00000749

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1460082 Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24 AN XY: 726202

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 85960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53076

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111262

Other (OTH) AF: 0.0000166 AC: 1 AN: 60294

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000825 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.080
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.24		Gain of helix (P = 0.0425)
MVP		0.78
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.14
gMVP		0.37
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs770792509; hg19: chr19-40978616; COSMIC: COSV58953694;