rs17652121

Variant names:

• chr17-45996607-T-C
• rs17652121
• NM_001377265.1:c.1941T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001377265.1(MAPT):​c.1941T>C​(p.Asn647Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,412 control chromosomes in the GnomAD database, including 32,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2148 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30650 hom.)
• Consequence: MAPT NM_001377265.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.0740
• Publications: 69 publications found

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 Gene-Disease associations (from GenCC):

• late-onset Parkinson disease

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Pick disease

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

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• progressive supranuclear palsy-parkinsonism syndrome

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-45996607-T-C is Benign according to our data. Variant chr17-45996607-T-C is described in ClinVar as Benign. ClinVar VariationId is 98209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.074 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377265.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	NM_001377265.1	MANE Select	c.1941T>C	p.Asn647Asn	synonymous	Exon 9 of 13	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.1770T>C	p.Asn590Asn	synonymous	Exon 11 of 15	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.1716T>C	p.Asn572Asn	synonymous	Exon 10 of 14	NP_058519.3	P10636-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	ENST00000262410.10	TSL:1 MANE Select	c.1941T>C	p.Asn647Asn	synonymous	Exon 9 of 13	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.1743T>C	p.Asn581Asn	synonymous	Exon 8 of 11	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.765T>C	p.Asn255Asn	synonymous	Exon 8 of 12	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22053 AN: 151688 Hom.: 2150 Cov.: 32

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0731

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.145 AC: 36129 AN: 249222 AF XY: 0.149

Gnomad AFR exome AF: 0.0472

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.194 AC: 282944 AN: 1461610 Hom.: 30650 Cov.: 53 AF XY: 0.191 AC XY: 138962 AN XY: 727102

African (AFR) AF: 0.0429 AC: 1435 AN: 33476

American (AMR) AF: 0.125 AC: 5612 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6699 AN: 26130

East Asian (EAS) AF: 0.000907 AC: 36 AN: 39694

South Asian (SAS) AF: 0.0796 AC: 6865 AN: 86250

European-Finnish (FIN) AF: 0.0724 AC: 3858 AN: 53324

Middle Eastern (MID) AF: 0.202 AC: 1165 AN: 5768

European-Non Finnish (NFE) AF: 0.222 AC: 246580 AN: 1111874

Other (OTH) AF: 0.177 AC: 10694 AN: 60374

GnomAD4 genome AF: 0.145 AC: 22043 AN: 151802 Hom.: 2148 Cov.: 32 AF XY: 0.136 AC XY: 10110 AN XY: 74194

African (AFR) AF: 0.0492 AC: 2038 AN: 41404

American (AMR) AF: 0.176 AC: 2678 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 832 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5152

South Asian (SAS) AF: 0.0732 AC: 351 AN: 4794

European-Finnish (FIN) AF: 0.0652 AC: 688 AN: 10550

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14746 AN: 67894

Other (OTH) AF: 0.184 AC: 386 AN: 2100

Alfa AF: 0.190 Hom.: 6815

Bravo AF: 0.150

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (3)
-	-	1	Frontotemporal dementia (1)
-	-	1	MAPT-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.9
DANN	Benign	0.59
PhyloP100		-0.074
Mutation Taster		=99/1	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: rs17652121; hg19: chr17-44073973;