rs193920967

Variant names:

• chr17-45962406-G-C
• rs193920967
• NM_001377265.1:c.69G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377265.1(MAPT):​c.69G>C​(p.Arg23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.35
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19190198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.69G>C	p.Arg23Ser	missense_variant	Exon 2 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.69G>C	p.Arg23Ser	missense_variant	Exon 2 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Prostate cancer Uncertain:1

-

Science for Life laboratory, Karolinska Institutet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	0.091
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;.;.;.;.;.
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;L;L;L;L;L;L;L;L;L
PhyloP100		2.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.60	N;N;N;N;N;N;N;N;N;.;.;.
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;.;.;.
Sift4G	Benign	0.081	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;P;D;.;P;P;P;P;D;D;P;.
Vest4		0.42
MutPred		0.12		Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);Loss of ubiquitination at K24 (P = 0.0598);
MVP		0.74
MPC		0.68
ClinPred		0.86	D
GERP RS		3.1
PromoterAI		0.0028	Neutral
Varity_R		0.20
gMVP		0.067

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: rs193920967; hg19: chr17-44039772; COSMIC: COSV52244319;