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):

• 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: 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).

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.69G>C	p.Arg23Ser	missense	Exon 2 of 13	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.69G>C	p.Arg23Ser	missense	Exon 2 of 15	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.69G>C	p.Arg23Ser	missense	Exon 2 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.69G>C	p.Arg23Ser	missense	Exon 2 of 13	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.69G>C	p.Arg23Ser	missense	Exon 2 of 11	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.69G>C	p.Arg23Ser	missense	Exon 2 of 12	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.091
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.081	T
Polyphen		0.99	D
Vest4		0.42
MutPred		0.12		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;