ENST00000579599.1:n.704G>C

Variant names:

• chr17-45894810-C-G
• rs3744456
• ENST00000579599.1:n.704G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000579599.1(MAPT-AS1):​n.704G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 152,594 control chromosomes in the GnomAD database, including 1,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1305 hom., cov: 32)
  • Exomes 𝑓: 0.14 (4 hom.)
• Consequence: MAPT-AS1 ENST00000579599.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0280
• Publications: 6 publications found

Genes affected

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

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 Gene-Disease associations (from GenCC):

• Pick disease

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• semantic dementia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• supranuclear palsy, progressive, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• progressive supranuclear palsy-parkinsonism syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-45894810-C-G is Benign according to our data. Variant chr17-45894810-C-G is described in ClinVar as Benign. ClinVar VariationId is 1168309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.-18+124C>G		intron_variant	Intron 1 of 12	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.-18+124C>G		intron_variant	Intron 1 of 12	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18912 AN: 152058 Hom.: 1295 Cov.: 32

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.136 AC: 57 AN: 418 Hom.: 4 Cov.: 0 AF XY: 0.142 AC XY: 44 AN XY: 310

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.250 AC: 1 AN: 4

South Asian (SAS) AF: 0.200 AC: 2 AN: 10

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AF: 0.250 AC: 2 AN: 8

European-Non Finnish (NFE) AF: 0.139 AC: 51 AN: 366

Other (OTH) AF: 0.0625 AC: 1 AN: 16

GnomAD4 genome AF: 0.124 AC: 18939 AN: 152176 Hom.: 1305 Cov.: 32 AF XY: 0.124 AC XY: 9201 AN XY: 74400

African (AFR) AF: 0.0694 AC: 2883 AN: 41558

American (AMR) AF: 0.167 AC: 2550 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3472

East Asian (EAS) AF: 0.148 AC: 757 AN: 5128

South Asian (SAS) AF: 0.103 AC: 497 AN: 4824

European-Finnish (FIN) AF: 0.142 AC: 1506 AN: 10610

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9762 AN: 67966

Other (OTH) AF: 0.149 AC: 315 AN: 2114

Alfa AF: 0.133 Hom.: 183

Bravo AF: 0.128

Asia WGS AF: 0.125 AC: 435 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.84
CADD	Benign	9.4
DANN	Benign	0.62
PhyloP100		0.028
PromoterAI		-0.022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3744456; hg19: chr17-43972176;