rs3744456

chr17-45894810-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001377265.1(MAPT):c.-18+124C>G variant causes a intron 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 NM_001377265.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0280

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 -14 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 id is 1168309.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
MAPT	NM_001377265.1	c.-18+124C>G		intron_variant		ENST00000262410.10
MAPT-AS1	NR_024559.1	n.34+670G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.-18+124C>G		intron_variant		1	NM_001377265.1	A2
MAPT-AS1	ENST00000634876.2	n.182+670G>C		intron_variant, non_coding_transcript_variant		5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.0625

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

Gnomad4 AFR AF: 0.0694

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.149

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Frontotemporal dementia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	9.4
Dann	Benign	0.62

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: rs3744456; hg19: chr17-43972176;