NM_001377265.1:c.220+2535A>G

Variant names:

• chr17-45974480-A-G
• rs1800547
• NM_001377265.1:c.220+2535A>G

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.220+2535A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,590,822 control chromosomes in the GnomAD database, including 32,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2144 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30243 hom.)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.04
• Publications: 88 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-45974480-A-G is Benign according to our data. Variant chr17-45974480-A-G is described in ClinVar as Benign. ClinVar VariationId is 257504.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	NM_001377265.1	MANE Select	c.220+2535A>G		intron	N/A	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.307+9A>G		intron	N/A	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.307+9A>G		intron	N/A	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.220+2535A>G		intron	N/A	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.220+2535A>G		intron	N/A	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.307+9A>G		intron	N/A	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22017 AN: 152096 Hom.: 2146 Cov.: 32

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.146 AC: 31207 AN: 214404 AF XY: 0.149

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000553

Gnomad FIN exome AF: 0.0661

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.193 AC: 277980 AN: 1438608 Hom.: 30243 Cov.: 31 AF XY: 0.191 AC XY: 136256 AN XY: 714074

African (AFR) AF: 0.0403 AC: 1337 AN: 33182

American (AMR) AF: 0.125 AC: 5224 AN: 41904

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6549 AN: 25636

East Asian (EAS) AF: 0.000897 AC: 35 AN: 39036

South Asian (SAS) AF: 0.0792 AC: 6600 AN: 83292

European-Finnish (FIN) AF: 0.0716 AC: 3650 AN: 50956

Middle Eastern (MID) AF: 0.202 AC: 1154 AN: 5718

European-Non Finnish (NFE) AF: 0.221 AC: 242885 AN: 1099368

Other (OTH) AF: 0.177 AC: 10546 AN: 59516

GnomAD4 genome AF: 0.145 AC: 22006 AN: 152214 Hom.: 2144 Cov.: 32 AF XY: 0.136 AC XY: 10088 AN XY: 74428

African (AFR) AF: 0.0478 AC: 1984 AN: 41548

American (AMR) AF: 0.175 AC: 2684 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3468

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.0741 AC: 357 AN: 4820

European-Finnish (FIN) AF: 0.0651 AC: 691 AN: 10610

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

European-Non Finnish (NFE) AF: 0.217 AC: 14749 AN: 67980

Other (OTH) AF: 0.182 AC: 384 AN: 2108

Alfa AF: 0.185 Hom.: 2245

Bravo AF: 0.150

Asia WGS AF: 0.0310 AC: 110 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 (2)
-	-	1	Frontotemporal dementia (1)
-	-	1	MAPT-Related Spectrum Disorders (1)
-	-	1	Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551863:Supranuclear palsy, progressive, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Benign	0.73
PhyloP100		1.0
Mutation Taster		=300/0	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: rs1800547; hg19: chr17-44051846;