NM_001377265.1:c.220+2613G>A

Variant names:

• chr17-45974558-G-A
• rs17651213
• NM_001377265.1:c.220+2613G>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.220+2613G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,068,254 control chromosomes in the GnomAD database, including 17,073 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2143 hom., cov: 32)
  • Exomes 𝑓: 0.17 (14930 hom.)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.773
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-45974558-G-A is Benign according to our data. Variant chr17-45974558-G-A is described in ClinVar as Benign. ClinVar VariationId is 1222027.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.220+2613G>A		intron_variant	Intron 3 of 12	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.220+2613G>A		intron_variant	Intron 3 of 12	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22020 AN: 152130 Hom.: 2145 Cov.: 32

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0734

Gnomad FIN AF: 0.0650

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.171 AC: 156937 AN: 916008 Hom.: 14930 Cov.: 12 AF XY: 0.170 AC XY: 79819 AN XY: 469688

African (AFR) AF: 0.0418 AC: 952 AN: 22748

American (AMR) AF: 0.130 AC: 4487 AN: 34500

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 5408 AN: 21630

East Asian (EAS) AF: 0.000741 AC: 25 AN: 33748

South Asian (SAS) AF: 0.0790 AC: 5499 AN: 69616

European-Finnish (FIN) AF: 0.0706 AC: 2897 AN: 41034

Middle Eastern (MID) AF: 0.205 AC: 791 AN: 3850

European-Non Finnish (NFE) AF: 0.201 AC: 129790 AN: 646638

Other (OTH) AF: 0.168 AC: 7088 AN: 42244

GnomAD4 genome AF: 0.145 AC: 22009 AN: 152246 Hom.: 2143 Cov.: 32 AF XY: 0.135 AC XY: 10085 AN XY: 74436

African (AFR) AF: 0.0478 AC: 1984 AN: 41546

American (AMR) AF: 0.176 AC: 2687 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3468

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

South Asian (SAS) AF: 0.0734 AC: 354 AN: 4820

European-Finnish (FIN) AF: 0.0650 AC: 691 AN: 10624

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

European-Non Finnish (NFE) AF: 0.217 AC: 14750 AN: 67990

Other (OTH) AF: 0.183 AC: 388 AN: 2116

Alfa AF: 0.198 Hom.: 1939

Bravo AF: 0.150

Asia WGS AF: 0.0310 AC: 111 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.61
PhyloP100		-0.77
Mutation Taster		=300/0	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: rs17651213; hg19: chr17-44051924;