rs63750417

chr17-45983409-C-Achr17-45983409-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001377265.1(MAPT):c.830C>A(p.Pro277Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,454,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. P277L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.432

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20751017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.830C>A	p.Pro277Gln	missense_variant	5/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.830C>A	p.Pro277Gln	missense_variant	5/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000209 AC: 5 AN: 239580 Hom.: 0 AF XY: 0.0000306 AC XY: 4 AN XY: 130826

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 SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1454038 Hom.: 0 Cov.: 34 AF XY: 0.00000969 AC XY: 7 AN XY: 722324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000249 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.29	T;.;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.69	T;T;.;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.29	N;N;N;.
REVEL	Benign	0.048
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.21
MutPred		0.51		Loss of glycosylation at P201 (P = 0.1774);Loss of glycosylation at P201 (P = 0.1774);Loss of glycosylation at P201 (P = 0.1774);Loss of glycosylation at P201 (P = 0.1774);
MVP		0.58
MPC		0.41
ClinPred		0.24	T
GERP RS		-0.93
Varity_R		0.043
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs63750417; hg19: chr17-44060775;