rs143956882

Positions:

• chr17-45989975-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001377265.1(MAPT):​c.1505C>T​(p.Ser502Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,206 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.40

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013220638).
• BP6: Variant 17-45989975-C-T is Benign according to our data. Variant chr17-45989975-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45989975-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00158 (240/152336) while in subpopulation NFE AF= 0.00235 (160/68032). AF 95% confidence interval is 0.00205. There are 1 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.1505C>T	p.Ser502Phe	missense_variant	7/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.1505C>T	p.Ser502Phe	missense_variant	7/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00166 AC: 417 AN: 251484 Hom.: 0 AF XY: 0.00159 AC XY: 216 AN XY: 135916

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00286

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00195 AC: 2849 AN: 1461870 Hom.: 9 Cov.: 32 AF XY: 0.00196 AC XY: 1423 AN XY: 727230

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00255

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74496

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00235

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00200 Hom.: 1

Bravo AF: 0.00143

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00146 AC: 177

EpiCase AF: 0.00229

EpiControl AF: 0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MAPT: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2019	This variant is associated with the following publications: (PMID: 27094865, 29887346, 27776828, 22312439, 30363439, 25937274) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T;T;.;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	2.0	M;M;M;M
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D;D;D;.
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.049	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.42
MVP		0.87
MPC		0.66
ClinPred		0.039	T
GERP RS		5.0
Varity_R		0.42
gMVP		0.20

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: rs143956882; hg19: chr17-44067341;