rs63750417

Variant names:

• chr17-45983409-C-T
• rs63750417
• NM_001377265.1:c.830C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-45983409-C-T
• chr17-45983409-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377265.1(MAPT):​c.830C>T​(p.Pro277Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,606,114 control chromosomes in the GnomAD database, including 32,668 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2145 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30523 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.432
• Publications: 56 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=0.0061332285).
• BP6: Variant 17-45983409-C-T is Benign according to our data. Variant chr17-45983409-C-T is described in ClinVar as Benign. ClinVar VariationId is 98244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

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.830C>T	p.Pro277Leu	missense	Exon 5 of 13	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.605C>T	p.Pro202Leu	missense	Exon 6 of 15	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.605C>T	p.Pro202Leu	missense	Exon 6 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.830C>T	p.Pro277Leu	missense	Exon 5 of 13	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.830C>T	p.Pro277Leu	missense	Exon 5 of 11	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.374-3631C>T		intron	N/A	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22080 AN: 152104 Hom.: 2147 Cov.: 32

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.146 AC: 35042 AN: 239580 AF XY: 0.150

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.000661

Gnomad FIN exome AF: 0.0691

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.194 AC: 281770 AN: 1453892 Hom.: 30523 Cov.: 34 AF XY: 0.191 AC XY: 138180 AN XY: 722234

African (AFR) AF: 0.0430 AC: 1432 AN: 33300

American (AMR) AF: 0.125 AC: 5538 AN: 44166

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6634 AN: 25872

East Asian (EAS) AF: 0.000885 AC: 35 AN: 39550

South Asian (SAS) AF: 0.0798 AC: 6845 AN: 85758

European-Finnish (FIN) AF: 0.0725 AC: 3771 AN: 52026

Middle Eastern (MID) AF: 0.202 AC: 1155 AN: 5724

European-Non Finnish (NFE) AF: 0.222 AC: 245727 AN: 1107568

Other (OTH) AF: 0.177 AC: 10633 AN: 59928

GnomAD4 genome AF: 0.145 AC: 22070 AN: 152222 Hom.: 2145 Cov.: 32 AF XY: 0.136 AC XY: 10132 AN XY: 74438

African (AFR) AF: 0.0491 AC: 2038 AN: 41544

American (AMR) AF: 0.176 AC: 2693 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5180

South Asian (SAS) AF: 0.0738 AC: 356 AN: 4822

European-Finnish (FIN) AF: 0.0652 AC: 692 AN: 10614

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14747 AN: 67974

Other (OTH) AF: 0.183 AC: 387 AN: 2114

Alfa AF: 0.172 Hom.: 1755

Bravo AF: 0.150

TwinsUK AF: 0.233 AC: 864

ALSPAC AF: 0.241 AC: 929

ESP6500AA AF: 0.0510 AC: 220

ESP6500EA AF: 0.222 AC: 1886

ExAC AF: 0.144 AC: 17428

Asia WGS AF: 0.0310 AC: 111 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (3)
-	-	1	Frontotemporal dementia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.43
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.030
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.11
MPC		0.16
ClinPred		0.012	T
GERP RS		-0.93
Varity_R		0.049
gMVP		0.11
Mutation Taster		=99/1	polymorphism (auto)

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: rs63750417; hg19: chr17-44060775;