rs150447798

Variant names:

• chr19-40472737-C-T
• rs150447798
• NM_020971.3:c.116C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020971.3(SPTBN4):​c.116C>T​(p.Ala39Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,606,964 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A39S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (10 hom.)
• Consequence: SPTBN4 NM_020971.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.39
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076540112).
• BP6: Variant 19-40472737-C-T is Benign according to our data. Variant chr19-40472737-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 770657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00227 (346/152130) while in subpopulation AMR AF = 0.00354 (54/15254). AF 95% confidence interval is 0.00312. There are 1 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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.116C>T	p.Ala39Val	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.116C>T	p.Ala39Val	missense	Exon 2 of 36	ENSP00000469242.1	Q9H254-1
	SPTBN4	ENST00000352632.7	TSL:5	c.116C>T	p.Ala39Val	missense	Exon 2 of 36	ENSP00000263373.2	Q9H254-1
	SPTBN4	ENST00000595535.5	TSL:5	c.116C>T	p.Ala39Val	missense	Exon 2 of 27	ENSP00000470693.1	M0QZQ3

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 345 AN: 152012 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00267 AC: 625 AN: 234124 AF XY: 0.00264

Gnomad AFR exome AF: 0.000341

Gnomad AMR exome AF: 0.00427

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000690

Gnomad NFE exome AF: 0.00345

Gnomad OTH exome AF: 0.00450

GnomAD4 exome AF: 0.00289 AC: 4199 AN: 1454834 Hom.: 10 Cov.: 33 AF XY: 0.00285 AC XY: 2062 AN XY: 723282

African (AFR) AF: 0.000479 AC: 16 AN: 33370

American (AMR) AF: 0.00430 AC: 189 AN: 43934

Ashkenazi Jewish (ASJ) AF: 0.00224 AC: 58 AN: 25886

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39550

South Asian (SAS) AF: 0.00185 AC: 158 AN: 85238

European-Finnish (FIN) AF: 0.000818 AC: 43 AN: 52540

Middle Eastern (MID) AF: 0.00900 AC: 51 AN: 5664

European-Non Finnish (NFE) AF: 0.00315 AC: 3490 AN: 1108644

Other (OTH) AF: 0.00322 AC: 193 AN: 60008

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152130 Hom.: 1 Cov.: 31 AF XY: 0.00190 AC XY: 141 AN XY: 74372

African (AFR) AF: 0.000602 AC: 25 AN: 41526

American (AMR) AF: 0.00354 AC: 54 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4814

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10594

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00349 AC: 237 AN: 67996

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00286 Hom.: 1

Bravo AF: 0.00264

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00248 AC: 301

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	SPTBN4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.28
Sift	Benign	0.044	D
Sift4G	Benign	0.12	T
Polyphen		0.67	P
Vest4		0.38
MVP		0.71
ClinPred		0.032	T
GERP RS		6.0
Varity_R		0.11
gMVP		0.25
Mutation Taster		=99/1	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: rs150447798; hg19: chr19-40978644; COSMIC: COSV58953326;