rs63751438

Variant names:

• chr17-46010388-C-G
• rs63751438
• NM_001377265.1:c.2077C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-46010388-C-G
• chr17-46010388-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_001377265.1(MAPT):​c.2077C>G​(p.Pro693Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P693S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.66
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001377265.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-46010388-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14256.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771
• PP5: Variant 17-46010388-C-G is Pathogenic according to our data. Variant chr17-46010388-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3075676.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.2077C>G	p.Pro693Ala	missense_variant	Exon 10 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.2077C>G	p.Pro693Ala	missense_variant	Exon 10 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Supranuclear palsy, progressive, 1 Pathogenic:1

Apr 27, 2023

Genomic Medicine Lab, University of California San Francisco

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;.;.;.;.;.;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;.;.;.;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.;M;.
PhyloP100		5.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D;D;.;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.028	D;T;D;T;D;T;D;.;.
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;B;D;D;D;D;D;D;B
Vest4		0.61
MutPred		0.88		Gain of catalytic residue at P618 (P = 0.0229);.;.;.;.;.;.;Gain of catalytic residue at P618 (P = 0.0229);.;
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.57
gMVP		0.97

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: rs63751438; hg19: chr17-44087754;