rs61741669

chr19-6496157-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006087.4(TUBB4A):c.342C>T(p.Asp114=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00617 in 1,614,102 control chromosomes in the GnomAD database, including 541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (292 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (249 hom.)
• Consequence: TUBB4A NM_006087.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.999

Genes affected

TUBB4A (HGNC:20774): (tubulin beta 4A class IVa) This gene encodes a member of the beta tubulin family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene cause hypomyelinating leukodystrophy-6 and autosomal dominant torsion dystonia-4. Alternate splicing results in multiple transcript variants encoding different isoforms. A pseudogene of this gene is found on chromosome X. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016824007).
• BP6: Variant 19-6496157-G-A is Benign according to our data. Variant chr19-6496157-G-A is described in ClinVar as [Benign]. Clinvar id is 330265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6496157-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.999 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4	c.342C>T	p.Asp114=	synonymous_variant	4/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4A	ENST00000264071.7	c.342C>T	p.Asp114=	synonymous_variant	4/4	1	NM_006087.4	P1

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5068 AN: 152102 Hom.: 291 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.00878 AC: 2208 AN: 251370 Hom.: 130 AF XY: 0.00636 AC XY: 864 AN XY: 135852

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00333 AC: 4875 AN: 1461882 Hom.: 249 Cov.: 33 AF XY: 0.00284 AC XY: 2062 AN XY: 727246

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.00653

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000211

Gnomad4 OTH exome AF: 0.00740

GnomAD4 genome AF: 0.0334 AC: 5083 AN: 152220 Hom.: 292 Cov.: 32 AF XY: 0.0325 AC XY: 2416 AN XY: 74428

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0184 Hom.: 56

Bravo AF: 0.0378

ESP6500AA AF: 0.114 AC: 502

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0107 AC: 1304

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Torsion dystonia 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	7.0
Dann	Benign	0.80
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0017	T;T
MutationTaster	Benign	1.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.23
GERP RS		-0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs61741669; hg19: chr19-6496168;