rs1052553

Variant names:

• chr17-45996523-A-G
• rs1052553
• NM_001377265.1:c.1857A>G

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.1857A>G​(p.Ala619Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,600,658 control chromosomes in the GnomAD database, including 32,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2153 hom., cov: 31)
  • Exomes 𝑓: 0.20 (30776 hom.)
• Consequence: MAPT NM_001377265.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -3.43
• Publications: 136 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=-0.85).
• BP6: Variant 17-45996523-A-G is Benign according to our data. Variant chr17-45996523-A-G is described in ClinVar as Benign. ClinVar VariationId is 98207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 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.1857A>G	p.Ala619Ala	synonymous	Exon 9 of 13	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.1686A>G	p.Ala562Ala	synonymous	Exon 11 of 15	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.1632A>G	p.Ala544Ala	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.1857A>G	p.Ala619Ala	synonymous	Exon 9 of 13	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.1659A>G	p.Ala553Ala	synonymous	Exon 8 of 11	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.681A>G	p.Ala227Ala	synonymous	Exon 8 of 12	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22120 AN: 150680 Hom.: 2155 Cov.: 31

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.00160

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.0667

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.145 AC: 35916 AN: 248312 AF XY: 0.148

Gnomad AFR exome AF: 0.0482

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000655

Gnomad FIN exome AF: 0.0678

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.196 AC: 283520 AN: 1449850 Hom.: 30776 Cov.: 53 AF XY: 0.193 AC XY: 139237 AN XY: 721366

African (AFR) AF: 0.0444 AC: 1476 AN: 33220

American (AMR) AF: 0.126 AC: 5613 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 6692 AN: 25926

East Asian (EAS) AF: 0.000898 AC: 35 AN: 38986

South Asian (SAS) AF: 0.0797 AC: 6866 AN: 86166

European-Finnish (FIN) AF: 0.0797 AC: 3853 AN: 48342

Middle Eastern (MID) AF: 0.203 AC: 1165 AN: 5730

European-Non Finnish (NFE) AF: 0.223 AC: 247108 AN: 1107220

Other (OTH) AF: 0.179 AC: 10712 AN: 59742

GnomAD4 genome AF: 0.147 AC: 22110 AN: 150808 Hom.: 2153 Cov.: 31 AF XY: 0.138 AC XY: 10132 AN XY: 73648

African (AFR) AF: 0.0503 AC: 2075 AN: 41230

American (AMR) AF: 0.177 AC: 2685 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 831 AN: 3452

East Asian (EAS) AF: 0.00161 AC: 8 AN: 4978

South Asian (SAS) AF: 0.0752 AC: 350 AN: 4654

European-Finnish (FIN) AF: 0.0667 AC: 684 AN: 10258

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.218 AC: 14776 AN: 67720

Other (OTH) AF: 0.183 AC: 385 AN: 2108

Alfa AF: 0.188 Hom.: 5098

Bravo AF: 0.151

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	-0.85
CADD	Benign	0.66
DANN	Benign	0.62
PhyloP100		-3.4
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: rs1052553; hg19: chr17-44073889;