rs9468

chr17-46024197-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377265.1(MAPT):c.*26T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,596,984 control chromosomes in the GnomAD database, including 32,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2145 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30494 hom.)
• Consequence: MAPT NM_001377265.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.46

Genes affected

MAPT (HGNC:6893): (microtubule associated protein tau) This gene encodes the microtubule-associated protein tau (MAPT) whose transcript undergoes complex, regulated alternative splicing, giving rise to several mRNA species. MAPT transcripts are differentially expressed in the nervous system, depending on stage of neuronal maturation and neuron type. MAPT gene mutations have been associated with several neurodegenerative disorders such as Alzheimer's disease, Pick's disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-46024197-T-C is Benign according to our data. Variant chr17-46024197-T-C is described in ClinVar as [Benign]. Clinvar id is 323650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46024197-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.*26T>C		3_prime_UTR_variant	13/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.*26T>C		3_prime_UTR_variant	13/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21882 AN: 151782 Hom.: 2147 Cov.: 32

Gnomad AFR AF: 0.0407

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.0802

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.146 AC: 36449 AN: 248996 Hom.: 3515 AF XY: 0.150 AC XY: 20240 AN XY: 135078

Gnomad AFR exome AF: 0.0379

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000655

Gnomad SAS exome AF: 0.0761

Gnomad FIN exome AF: 0.0812

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.195 AC: 281126 AN: 1445084 Hom.: 30494 Cov.: 28 AF XY: 0.192 AC XY: 138276 AN XY: 720062

Gnomad4 AFR exome AF: 0.0345

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.000884

Gnomad4 SAS exome AF: 0.0796

Gnomad4 FIN exome AF: 0.0859

Gnomad4 NFE exome AF: 0.223

Gnomad4 OTH exome AF: 0.178

GnomAD4 genome AF: 0.144 AC: 21870 AN: 151900 Hom.: 2145 Cov.: 32 AF XY: 0.135 AC XY: 10048 AN XY: 74266

Gnomad4 AFR AF: 0.0405

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0742

Gnomad4 FIN AF: 0.0802

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.182

Alfa AF: 0.196 Hom.: 844

Bravo AF: 0.147

Asia WGS AF: 0.0300 AC: 106 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MAPT-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	9.5
Dann	Benign	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

Publications

LitVar

Other links and lift over

dbSNP: rs9468; hg19: chr17-44101563;