NM_001377265.1:c.1704G>A

Variant names:

• chr17-45991558-G-A
• rs1052551
• NM_001377265.1:c.1704G>A

Variant summary

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

The NM_001377265.1(MAPT):​c.1704G>A​(p.Pro568Pro) 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 1,613,892 control chromosomes in the GnomAD database, including 32,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P568P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2121 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30642 hom.)
• Consequence: MAPT NM_001377265.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -2.84
• Publications: 49 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):

• 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=-0.78).
• BP6: Variant 17-45991558-G-A is Benign according to our data. Variant chr17-45991558-G-A is described in ClinVar as Benign. ClinVar VariationId is 98204.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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	NM_001377265.1	MANE Select	c.1704G>A	p.Pro568Pro	synonymous	Exon 8 of 13	NP_001364194.1
	MAPT	NM_001123066.4		c.1479G>A	p.Pro493Pro	synonymous	Exon 9 of 15	NP_001116538.2
	MAPT	NM_016835.5		c.1479G>A	p.Pro493Pro	synonymous	Exon 9 of 14	NP_058519.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	ENST00000262410.10	TSL:1 MANE Select	c.1704G>A	p.Pro568Pro	synonymous	Exon 8 of 13	ENSP00000262410.6
	MAPT	ENST00000344290.10	TSL:1	c.1506G>A	p.Pro502Pro	synonymous	Exon 7 of 11	ENSP00000340820.6
	MAPT	ENST00000351559.10	TSL:1	c.528G>A	p.Pro176Pro	synonymous	Exon 7 of 12	ENSP00000303214.7

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21640 AN: 152022 Hom.: 2123 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.145 AC: 36413 AN: 251260 AF XY: 0.149

Gnomad AFR exome AF: 0.0361

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000761

Gnomad FIN exome AF: 0.0681

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.193 AC: 282608 AN: 1461752 Hom.: 30642 Cov.: 35 AF XY: 0.191 AC XY: 138832 AN XY: 727176

African (AFR) AF: 0.0334 AC: 1119 AN: 33478

American (AMR) AF: 0.125 AC: 5597 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6698 AN: 26134

East Asian (EAS) AF: 0.000907 AC: 36 AN: 39700

South Asian (SAS) AF: 0.0795 AC: 6859 AN: 86256

European-Finnish (FIN) AF: 0.0724 AC: 3869 AN: 53410

Middle Eastern (MID) AF: 0.201 AC: 1160 AN: 5766

European-Non Finnish (NFE) AF: 0.222 AC: 246604 AN: 1111900

Other (OTH) AF: 0.177 AC: 10666 AN: 60388

GnomAD4 genome AF: 0.142 AC: 21627 AN: 152140 Hom.: 2121 Cov.: 32 AF XY: 0.133 AC XY: 9889 AN XY: 74376

African (AFR) AF: 0.0391 AC: 1623 AN: 41516

American (AMR) AF: 0.175 AC: 2681 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5180

South Asian (SAS) AF: 0.0738 AC: 356 AN: 4822

European-Finnish (FIN) AF: 0.0651 AC: 690 AN: 10598

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

European-Non Finnish (NFE) AF: 0.217 AC: 14744 AN: 67960

Other (OTH) AF: 0.178 AC: 375 AN: 2102

Alfa AF: 0.190 Hom.: 4465

Bravo AF: 0.147

ClinVar

ClinVar submissions as Germline

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	-0.78
CADD	Benign	0.87
DANN	Benign	0.61
PhyloP100		-2.8
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: rs1052551; hg19: chr17-44068924;