rs63750222

Variant names:

• chr17-45983659-C-A
• rs63750222
• NM_001377265.1:c.1080C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-45983659-C-A
• chr17-45983659-C-G
• chr17-45983659-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377265.1(MAPT):​c.1080C>A​(p.Asp360Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D360N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.11
• Publications: 25 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03590563).

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.1080C>A	p.Asp360Glu	missense	Exon 5 of 13	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.855C>A	p.Asp285Glu	missense	Exon 6 of 15	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.855C>A	p.Asp285Glu	missense	Exon 6 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.1080C>A	p.Asp360Glu	missense	Exon 5 of 13	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.1080C>A	p.Asp360Glu	missense	Exon 5 of 11	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.374-3381C>A		intron	N/A	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250932 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461694 Hom.: 0 Cov.: 49 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0010
DANN	Benign	0.60
DEOGEN2	Benign	0.27	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.42	N
PhyloP100		-4.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.015
Sift	Benign	0.87	T
Sift4G	Benign	0.96	T
Polyphen		0.0	B
Vest4		0.0070
MutPred		0.19		Gain of glycosylation at P284 (P = 0.095)
MVP		0.48
MPC		0.14
ClinPred		0.060	T
GERP RS		-11
Varity_R		0.035
gMVP		0.032

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: rs63750222; hg19: chr17-44061025;