17-45991562-G-A

Variant names:

• chr17-45991562-G-A
• rs63750612
• NM_001377265.1:c.1708G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001377265.1(MAPT):​c.1708G>A​(p.Ala570Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,614,058 control chromosomes in the GnomAD database, including 100 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (56 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.997
• Publications: 20 publications found

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]

MAPT Gene-Disease associations (from GenCC):

• late-onset Parkinson disease

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Pick disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• semantic dementia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• supranuclear palsy, progressive, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• progressive supranuclear palsy-parkinsonism syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019565523).
• BP6: Variant 17-45991562-G-A is Benign according to our data. Variant chr17-45991562-G-A is described in ClinVar as Benign. ClinVar VariationId is 98205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2152/152232) while in subpopulation AFR AF = 0.0491 (2040/41524). AF 95% confidence interval is 0.0474. There are 44 homozygotes in GnomAd4. There are 1000 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377265.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	NM_001377265.1	MANE Select	c.1708G>A	p.Ala570Thr	missense	Exon 8 of 13	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.1483G>A	p.Ala495Thr	missense	Exon 9 of 15	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.1483G>A	p.Ala495Thr	missense	Exon 9 of 14	NP_058519.3	P10636-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	ENST00000262410.10	TSL:1 MANE Select	c.1708G>A	p.Ala570Thr	missense	Exon 8 of 13	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.1510G>A	p.Ala504Thr	missense	Exon 7 of 11	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.532G>A	p.Ala178Thr	missense	Exon 7 of 12	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2154 AN: 152114 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.00364 AC: 915 AN: 251212 AF XY: 0.00264

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00141 AC: 2061 AN: 1461826 Hom.: 56 Cov.: 33 AF XY: 0.00117 AC XY: 851 AN XY: 727212

African (AFR) AF: 0.0499 AC: 1671 AN: 33474

American (AMR) AF: 0.00302 AC: 135 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111984

Other (OTH) AF: 0.00321 AC: 194 AN: 60388

GnomAD4 genome AF: 0.0141 AC: 2152 AN: 152232 Hom.: 44 Cov.: 32 AF XY: 0.0134 AC XY: 1000 AN XY: 74430

African (AFR) AF: 0.0491 AC: 2040 AN: 41524

American (AMR) AF: 0.00549 AC: 84 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.00540 Hom.: 39

Bravo AF: 0.0162

ESP6500AA AF: 0.0454 AC: 200

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00421 AC: 511

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (3)
-	-	1	Frontotemporal dementia (1)
-	-	1	MAPT-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.28
DANN	Benign	0.85
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.41	N
PhyloP100		-1.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.0050
Sift	Benign	0.43	T
Sift4G	Benign	0.69	T
Polyphen		0.010	B
Vest4		0.029
MVP		0.30
MPC		0.15
ClinPred		0.0023	T
GERP RS		-8.8
Varity_R		0.026
gMVP		0.14
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs63750612; hg19: chr17-44068928; COSMIC: COSV52248827; COSMIC: COSV52248827;