rs76375268

chr17-45983441-G-A

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.862G>A(p.Gly288Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,606,902 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (36 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.180

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=0.0036166906).
• BP6: Variant 17-45983441-G-A is Benign according to our data. Variant chr17-45983441-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 529747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45983441-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0104 (1583/152306) while in subpopulation AFR AF= 0.0328 (1364/41578). AF 95% confidence interval is 0.0314. There are 33 homozygotes in gnomad4. There are 710 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.862G>A	p.Gly288Arg	missense_variant	5/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.862G>A	p.Gly288Arg	missense_variant	5/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1562 AN: 152190 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00342 AC: 826 AN: 241626 Hom.: 10 AF XY: 0.00272 AC XY: 358 AN XY: 131674

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.0000476

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00192 AC: 2800 AN: 1454596 Hom.: 36 Cov.: 34 AF XY: 0.00177 AC XY: 1279 AN XY: 722666

Gnomad4 AFR exome AF: 0.0324

Gnomad4 AMR exome AF: 0.00433

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.0000768

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.00453

GnomAD4 genome AF: 0.0104 AC: 1583 AN: 152306 Hom.: 33 Cov.: 32 AF XY: 0.00953 AC XY: 710 AN XY: 74470

Gnomad4 AFR AF: 0.0328

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00252 Hom.: 4

Bravo AF: 0.0119

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0285 AC: 125

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00384 AC: 466

Asia WGS AF: 0.00520 AC: 18 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Frontotemporal dementia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.66	T;T;.;.
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.1	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	0.25	T
PROVEAN	Benign	-1.4	N;N;N;.
REVEL	Benign	0.027
Sift	Benign	0.056	T;D;D;.
Sift4G	Benign	0.63	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.10
MutPred		0.33		Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);
MVP		0.63
MPC		0.25
ClinPred		0.025	T
GERP RS		1.1
Varity_R		0.044
gMVP		0.087

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: rs76375268; hg19: chr17-44060807;