chr19-40472853-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020971.3(SPTBN4):​c.169+63C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000634 in 1,262,444 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000063 (1 hom.)
• Consequence: SPTBN4 NM_020971.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000634 AC: 8 AN: 1262444 Hom.: 1 AF XY: 0.00000486 AC XY: 3 AN XY: 616856

African (AFR) AF: 0.00 AC: 0 AN: 27604

American (AMR) AF: 0.000179 AC: 5 AN: 27978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20588

East Asian (EAS) AF: 0.00 AC: 0 AN: 34324

South Asian (SAS) AF: 0.00 AC: 0 AN: 68958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3602

European-Non Finnish (NFE) AF: 0.00000305 AC: 3 AN: 983220

Other (OTH) AF: 0.00 AC: 0 AN: 51920

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 190

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.71
PhyloP100		-0.63

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;