rs2435203

Variant names:

• chr17-46005931-T-C
• rs2435203
• NM_001377265.1:c.1999-4379T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377265.1(MAPT):​c.1999-4379T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 152,242 control chromosomes in the GnomAD database, including 2,656 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2656 hom., cov: 33)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.257
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.578 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.1999-4379T>C		intron	N/A	NP_001364194.1
	MAPT	NM_001123066.4		c.1828-4379T>C		intron	N/A	NP_001116538.2
	MAPT	NM_016835.5		c.1774-4379T>C		intron	N/A	NP_058519.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	ENST00000262410.10	TSL:1 MANE Select	c.1999-4379T>C		intron	N/A	ENSP00000262410.6
	MAPT	ENST00000344290.10	TSL:1	c.1801-8312T>C		intron	N/A	ENSP00000340820.6
	MAPT	ENST00000351559.10	TSL:1	c.823-4379T>C		intron	N/A	ENSP00000303214.7

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24612 AN: 152124 Hom.: 2644 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.160

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.162 AC: 24647 AN: 152242 Hom.: 2656 Cov.: 33 AF XY: 0.170 AC XY: 12661 AN XY: 74444

African (AFR) AF: 0.137 AC: 5705 AN: 41546

American (AMR) AF: 0.235 AC: 3597 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 502 AN: 3472

East Asian (EAS) AF: 0.595 AC: 3080 AN: 5176

South Asian (SAS) AF: 0.216 AC: 1043 AN: 4828

European-Finnish (FIN) AF: 0.179 AC: 1901 AN: 10602

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8323 AN: 68014

Other (OTH) AF: 0.169 AC: 357 AN: 2114

Alfa AF: 0.143 Hom.: 3542

Bravo AF: 0.165

Asia WGS AF: 0.394 AC: 1368 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.7
DANN	Benign	0.74
PhyloP100		0.26
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: rs2435203; hg19: chr17-44083297;