rs63750013

chr17-46010405-G-Achr17-46010405-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001377265.1(MAPT):c.2091+3G>A variant causes a splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAPT NM_001377265.1 splice_donor_region, intron
• Scores: Splicing: ADA: 0.07189
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 5.33

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-46010405-G-A is Pathogenic according to our data. Variant chr17-46010405-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46010405-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.2091+3G>A		splice_donor_region_variant, intron_variant		ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.2091+3G>A		splice_donor_region_variant, intron_variant		1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1411796 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 697870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 15, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2022	Published functional studies demonstrate an increase in four-repeat over three-repeat tau isoforms, which leads to formation of abnormal tau filaments (Spillantini et al., 1998); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25556536, 22818528, 32184751, 16008820, 21753165, 30996196, 25525159, 9636220, 19786698, 10931371, 21849646, 21568901, 25628962, 25574752, 21986680, 25683866, 27222125, 22290573, 34274155, 33203472, 34099697) -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.072
dbscSNV1_RF	Benign	0.38
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: rs63750013; hg19: chr17-44087771;