19-40472853-C-T

Variant names:

• chr19-40472853-C-T
• rs62106997
• NM_020971.3:c.169+63C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020971.3(SPTBN4):​c.169+63C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,412,712 control chromosomes in the GnomAD database, including 18,997 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3018 hom., cov: 30)
  • Exomes 𝑓: 0.14 (15979 hom.)
• Consequence: SPTBN4 NM_020971.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.633
• Publications: 0 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 (BayesDel_noAF=-0.85).
• BP6: Variant 19-40472853-C-T is Benign according to our data. Variant chr19-40472853-C-T is described in ClinVar as Benign. ClinVar VariationId is 1224590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

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.169+63C>T		intron	N/A	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.169+63C>T		intron	N/A	ENSP00000469242.1	Q9H254-1
	SPTBN4	ENST00000352632.7	TSL:5	c.169+63C>T		intron	N/A	ENSP00000263373.2	Q9H254-1
	SPTBN4	ENST00000595535.5	TSL:5	c.169+63C>T		intron	N/A	ENSP00000470693.1	M0QZQ3

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27840 AN: 151508 Hom.: 3011 Cov.: 30

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.00617

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.0930

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.200

GnomAD4 exome AF: 0.143 AC: 180771 AN: 1261090 Hom.: 15979 AF XY: 0.146 AC XY: 90018 AN XY: 616152

African (AFR) AF: 0.287 AC: 7918 AN: 27554

American (AMR) AF: 0.0968 AC: 2704 AN: 27940

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2399 AN: 20568

East Asian (EAS) AF: 0.00355 AC: 122 AN: 34324

South Asian (SAS) AF: 0.224 AC: 15388 AN: 68780

European-Finnish (FIN) AF: 0.0982 AC: 4342 AN: 44212

Middle Eastern (MID) AF: 0.179 AC: 645 AN: 3598

European-Non Finnish (NFE) AF: 0.142 AC: 139663 AN: 982256

Other (OTH) AF: 0.146 AC: 7590 AN: 51858

GnomAD4 genome AF: 0.184 AC: 27880 AN: 151622 Hom.: 3018 Cov.: 30 AF XY: 0.179 AC XY: 13292 AN XY: 74124

African (AFR) AF: 0.291 AC: 11990 AN: 41240

American (AMR) AF: 0.129 AC: 1962 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 453 AN: 3466

East Asian (EAS) AF: 0.00599 AC: 31 AN: 5176

South Asian (SAS) AF: 0.222 AC: 1063 AN: 4794

European-Finnish (FIN) AF: 0.0930 AC: 980 AN: 10534

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10783 AN: 67886

Other (OTH) AF: 0.199 AC: 418 AN: 2104

Alfa AF: 0.103 Hom.: 190

Bravo AF: 0.189

Asia WGS AF: 0.118 AC: 410 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.62
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism (auto)

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: rs62106997; hg19: chr19-40978760; COSMIC: COSV58951212;