rs63751443

Variant names:

• chr17-46010431-G-A
• rs63751443
• NM_001377265.1:c.2091+29G>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.2091+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,460,154 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (12 hom.)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -1.06
• Publications: 0 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 (BayesDel_noAF=-0.83).
• BP6: Variant 17-46010431-G-A is Benign according to our data. Variant chr17-46010431-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 98225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00205 (312/152286) while in subpopulation NFE AF = 0.00334 (227/68030). AF 95% confidence interval is 0.00298. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 Unknown,AR,AD 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.2091+29G>A		intron	N/A	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.1920+29G>A		intron	N/A	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.1866+29G>A		intron	N/A	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.2091+29G>A		intron	N/A	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.1801-3812G>A		intron	N/A	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.915+29G>A		intron	N/A	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00208 AC: 338 AN: 162322 AF XY: 0.00205

Gnomad AFR exome AF: 0.000744

Gnomad AMR exome AF: 0.000918

Gnomad ASJ exome AF: 0.00489

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000701

Gnomad NFE exome AF: 0.00370

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00354 AC: 4628 AN: 1307868 Hom.: 12 Cov.: 20 AF XY: 0.00338 AC XY: 2199 AN XY: 650458

African (AFR) AF: 0.000696 AC: 21 AN: 30160

American (AMR) AF: 0.000806 AC: 29 AN: 35968

Ashkenazi Jewish (ASJ) AF: 0.00504 AC: 124 AN: 24582

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36190

South Asian (SAS) AF: 0.000567 AC: 44 AN: 77608

European-Finnish (FIN) AF: 0.000424 AC: 21 AN: 49568

Middle Eastern (MID) AF: 0.00163 AC: 9 AN: 5538

European-Non Finnish (NFE) AF: 0.00421 AC: 4178 AN: 993334

Other (OTH) AF: 0.00366 AC: 201 AN: 54920

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74448

African (AFR) AF: 0.000746 AC: 31 AN: 41558

American (AMR) AF: 0.00131 AC: 20 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00334 AC: 227 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00298 Hom.: 2

Bravo AF: 0.00218

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (6)
-	-	1	Frontotemporal dementia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	MAPT-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.87
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63751443; hg19: chr17-44087797;