rs62063845

Variant names:

• chr17-45993928-T-C
• rs62063845
• NM_001377265.1:c.1732+2342T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001377265.1(MAPT):​c.1732+2342T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,571,794 control chromosomes in the GnomAD database, including 32,173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2142 hom., cov: 33)
  • Exomes 𝑓: 0.19 (30031 hom.)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.732
• Publications: 26 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):

• Pick disease

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

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• progressive supranuclear palsy-parkinsonism syndrome

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-45993928-T-C is Benign according to our data. Variant chr17-45993928-T-C is described in ClinVar as Benign. ClinVar VariationId is 98206.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	NM_001377265.1	MANE Select	c.1732+2342T>C		intron	N/A	NP_001364194.1
	MAPT	NM_001123066.4		c.1512T>C	p.Thr504Thr	synonymous	Exon 10 of 15	NP_001116538.2
	MAPT	NM_016835.5		c.1507+2342T>C		intron	N/A	NP_058519.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	ENST00000262410.10	TSL:1 MANE Select	c.1732+2342T>C		intron	N/A	ENSP00000262410.6
	MAPT	ENST00000344290.10	TSL:1	c.1534+2342T>C		intron	N/A	ENSP00000340820.6
	MAPT	ENST00000351559.10	TSL:1	c.556+2342T>C		intron	N/A	ENSP00000303214.7

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22072 AN: 152134 Hom.: 2144 Cov.: 33

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.145 AC: 27044 AN: 186804 AF XY: 0.147

Gnomad AFR exome AF: 0.0457

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.000589

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.195 AC: 276451 AN: 1419542 Hom.: 30031 Cov.: 33 AF XY: 0.192 AC XY: 135004 AN XY: 702404

African (AFR) AF: 0.0429 AC: 1392 AN: 32456

American (AMR) AF: 0.128 AC: 4970 AN: 38756

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6519 AN: 25462

East Asian (EAS) AF: 0.000879 AC: 33 AN: 37526

South Asian (SAS) AF: 0.0800 AC: 6463 AN: 80806

European-Finnish (FIN) AF: 0.0720 AC: 3644 AN: 50618

Middle Eastern (MID) AF: 0.203 AC: 1156 AN: 5708

European-Non Finnish (NFE) AF: 0.222 AC: 241805 AN: 1089460

Other (OTH) AF: 0.178 AC: 10469 AN: 58750

GnomAD4 genome AF: 0.145 AC: 22062 AN: 152252 Hom.: 2142 Cov.: 33 AF XY: 0.136 AC XY: 10120 AN XY: 74454

African (AFR) AF: 0.0492 AC: 2044 AN: 41570

American (AMR) AF: 0.176 AC: 2687 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5184

South Asian (SAS) AF: 0.0735 AC: 355 AN: 4828

European-Finnish (FIN) AF: 0.0649 AC: 689 AN: 10614

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.217 AC: 14745 AN: 67978

Other (OTH) AF: 0.182 AC: 385 AN: 2112

Alfa AF: 0.198 Hom.: 2312

Bravo AF: 0.150

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	10
DANN	Benign	0.35
PhyloP100		0.73
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62063845; hg19: chr17-44071294;