rs34004825

Variant names:

• chr19-40472546-G-A
• rs34004825
• NM_020971.3:c.-15-61G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-40472546-G-A
• chr19-40472546-G-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.-15-61G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,451,080 control chromosomes in the GnomAD database, including 14,879 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2531 hom., cov: 31)
  • Exomes 𝑓: 0.13 (12348 hom.)
• Consequence: SPTBN4 NM_020971.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 19-40472546-G-A is Benign according to our data. Variant chr19-40472546-G-A is described in ClinVar as Benign. ClinVar VariationId is 1260689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 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.-15-61G>A		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.-15-61G>A		intron	N/A	ENSP00000469242.1	Q9H254-1
	SPTBN4	ENST00000352632.7	TSL:5	c.-15-61G>A		intron	N/A	ENSP00000263373.2	Q9H254-1
	SPTBN4	ENST00000595535.5	TSL:5	c.-15-61G>A		intron	N/A	ENSP00000470693.1	M0QZQ3

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25542 AN: 152026 Hom.: 2531 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.134 AC: 174063 AN: 1298936 Hom.: 12348 AF XY: 0.134 AC XY: 85369 AN XY: 634788

African (AFR) AF: 0.281 AC: 8254 AN: 29322

American (AMR) AF: 0.0862 AC: 2314 AN: 26846

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 4519 AN: 19966

East Asian (EAS) AF: 0.127 AC: 4628 AN: 36362

South Asian (SAS) AF: 0.149 AC: 10158 AN: 68346

European-Finnish (FIN) AF: 0.109 AC: 5192 AN: 47454

Middle Eastern (MID) AF: 0.245 AC: 1290 AN: 5256

European-Non Finnish (NFE) AF: 0.128 AC: 129411 AN: 1011592

Other (OTH) AF: 0.154 AC: 8297 AN: 53792

GnomAD4 genome AF: 0.168 AC: 25553 AN: 152144 Hom.: 2531 Cov.: 31 AF XY: 0.166 AC XY: 12354 AN XY: 74384

African (AFR) AF: 0.272 AC: 11289 AN: 41494

American (AMR) AF: 0.111 AC: 1693 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 759 AN: 3472

East Asian (EAS) AF: 0.151 AC: 784 AN: 5182

South Asian (SAS) AF: 0.145 AC: 699 AN: 4828

European-Finnish (FIN) AF: 0.104 AC: 1102 AN: 10612

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.129 AC: 8761 AN: 67988

Other (OTH) AF: 0.172 AC: 364 AN: 2116

Alfa AF: 0.128 Hom.: 658

Bravo AF: 0.173

Asia WGS AF: 0.150 AC: 523 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	-0.63
CADD	Benign	8.6
DANN	Benign	0.83
PhyloP100		1.6
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: rs34004825; hg19: chr19-40978453;