17-45894571-C-A

Variant names:

• chr17-45894571-C-A
• rs62056779
• NM_001377265.1:c.-133C>A

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.-133C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 153,856 control chromosomes in the GnomAD database, including 2,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2131 hom., cov: 32)
  • Exomes 𝑓: 0.13 (23 hom.)
• Consequence: MAPT NM_001377265.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.69

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]

MAPT-AS1 (HGNC:43738): (MAPT antisense RNA 1) Implicated in Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 17-45894571-C-A is Benign according to our data. Variant chr17-45894571-C-A is described in ClinVar as [Benign]. Clinvar id is 323639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.-133C>A		5_prime_UTR_variant	Exon 1 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410	c.-133C>A		5_prime_UTR_variant	Exon 1 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21808 AN: 152000 Hom.: 2133 Cov.: 32

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.0645

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.128 AC: 223 AN: 1744 Hom.: 23 Cov.: 0 AF XY: 0.132 AC XY: 162 AN XY: 1230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.100

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.0263

Gnomad4 SAS exome AF: 0.0638

Gnomad4 FIN exome AF: 0.0877

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.143 AC: 21798 AN: 152112 Hom.: 2131 Cov.: 32 AF XY: 0.134 AC XY: 9976 AN XY: 74376

Gnomad4 AFR AF: 0.0430

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0742

Gnomad4 FIN AF: 0.0645

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.182

Alfa AF: 0.165 Hom.: 303

Bravo AF: 0.148

Asia WGS AF: 0.0300 AC: 105 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MAPT-Related Spectrum Disorders Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	21
DANN	Benign	0.75

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: rs62056779; hg19: chr17-43971937;