17-45962387-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001377265.1(MAPT):c.50C>T(p.Thr17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,612,588 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (1 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.353

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011078745).
• BP6: Variant 17-45962387-C-T is Benign according to our data. Variant chr17-45962387-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 704535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45962387-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000756 (115/152176) while in subpopulation AFR AF= 0.0027 (112/41528). AF 95% confidence interval is 0.00229. There are 0 homozygotes in gnomad4. There are 57 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.50C>T	p.Thr17Met	missense_variant	2/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.50C>T	p.Thr17Met	missense_variant	2/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251100 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135722

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000918 AC: 134 AN: 1460412 Hom.: 1 Cov.: 33 AF XY: 0.0000826 AC XY: 60 AN XY: 726520

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000756 AC: 115 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74402

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.000790

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 07, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2020

This variant is associated with the following publications: (PMID: 25174650, 20020531) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.32	T;.;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.83	T;T;T;T;D;T;T;.;.;.;.;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.69	N;N;N;N;N;N;N;N;N;.;.;.
REVEL	Benign	0.098
Sift	Uncertain	0.011	D;D;D;D;D;T;T;D;D;.;.;.
Sift4G	Uncertain	0.032	D;T;D;T;T;T;T;T;D;D;T;T
Polyphen		0.99	D;D;D;.;D;P;P;D;D;D;D;.
Vest4		0.12
MVP		0.58
MPC		0.40
ClinPred		0.078	T
GERP RS		0.52
Varity_R		0.11
gMVP		0.033

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144611688; hg19: chr17-44039753;