NM_001377265.1:c.1999-6612A>G

Variant names:

• chr17-46003698-A-G
• rs8070723
• NM_001377265.1:c.1999-6612A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377265.1(MAPT):​c.1999-6612A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,218 control chromosomes in the GnomAD database, including 2,746 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2746 hom., cov: 32)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510
• Publications: 175 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.1999-6612A>G		intron_variant	Intron 9 of 12	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.1999-6612A>G		intron_variant	Intron 9 of 12	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27234 AN: 152100 Hom.: 2741 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0745

Gnomad FIN AF: 0.0639

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.209

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.179 AC: 27254 AN: 152218 Hom.: 2746 Cov.: 32 AF XY: 0.170 AC XY: 12619 AN XY: 74428

African (AFR) AF: 0.167 AC: 6947 AN: 41510

American (AMR) AF: 0.186 AC: 2851 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 837 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.0744 AC: 359 AN: 4828

European-Finnish (FIN) AF: 0.0639 AC: 679 AN: 10624

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14820 AN: 67992

Other (OTH) AF: 0.205 AC: 434 AN: 2112

Alfa AF: 0.204 Hom.: 13030

Bravo AF: 0.190

Asia WGS AF: 0.0390 AC: 137 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.44
PhyloP100		0.051
Mutation Taster		=100/0	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: rs8070723; hg19: chr17-44081064;