rs63750959

chr17-45962351-G-Achr17-45962351-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5 BP4_Moderate BS1

The NM_001377265.1(MAPT):c.14G>A(p.Arg5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,611,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 2.91

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 -4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-45962351-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14263.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07977325).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000329 (5/152102) while in subpopulation EAS AF= 0.000968 (5/5166). AF 95% confidence interval is 0.000381. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.14G>A	p.Arg5His	missense_variant	2/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.14G>A	p.Arg5His	missense_variant	2/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000598 AC: 15 AN: 250966 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000761

Gnomad SAS 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: 0.0000233 AC: 34 AN: 1459828 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 726226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Frontotemporal dementia Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 21, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5 of the MAPT protein (p.Arg5His). This variant is present in population databases (rs63750959, gnomAD 0.06%). This missense change has been observed in individuals with MAPT-related conditions (PMID: 11921059, 22312439, 26200045, 26601740, 28462717, 28923025, 33580635). ClinVar contains an entry for this variant (Variation ID: 14261). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MAPT function (PMID: 11921059). This variant disrupts the p.Arg5 amino acid residue in MAPT. Other variant(s) that disrupt this residue have been observed in individuals with MAPT-related conditions (PMID: 12325083, 18803694, 23043292), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

MAPT-Related Spectrum Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.32	T;.;.;.;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;.;.;.;.;.
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.080	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.8	L;L;L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.98	N;N;N;N;N;N;N;N;N;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.17	T;T;T;T;T;D;D;T;T;.;.;.
Sift4G	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.94	P;P;P;.;D;D;D;D;P;P;P;.
Vest4		0.30
MVP		0.89
MPC		0.73
ClinPred		0.30	T
GERP RS		4.2
Varity_R		0.046
gMVP		0.15

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: rs63750959; hg19: chr17-44039717;