17-45971963-C-T

Variant names:

• chr17-45971963-C-T
• rs75242405
• NM_001377265.1:c.220+18C>T

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+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,601,192 control chromosomes in the GnomAD database, including 32,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2141 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30553 hom.)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.603
• Publications: 16 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=-0.78).
• BP6: Variant 17-45971963-C-T is Benign according to our data. Variant chr17-45971963-C-T is described in ClinVar as Benign. ClinVar VariationId is 257503.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.220+18C>T		intron	N/A	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.220+18C>T		intron	N/A	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.220+18C>T		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.220+18C>T		intron	N/A	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.220+18C>T		intron	N/A	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.220+18C>T		intron	N/A	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22005 AN: 152060 Hom.: 2143 Cov.: 32

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0650

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.145 AC: 36282 AN: 249538 AF XY: 0.149

Gnomad AFR exome AF: 0.0454

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000654

Gnomad FIN exome AF: 0.0681

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.194 AC: 281334 AN: 1449014 Hom.: 30553 Cov.: 29 AF XY: 0.192 AC XY: 138258 AN XY: 721602

African (AFR) AF: 0.0408 AC: 1357 AN: 33226

American (AMR) AF: 0.125 AC: 5596 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 6688 AN: 26062

East Asian (EAS) AF: 0.000908 AC: 36 AN: 39632

South Asian (SAS) AF: 0.0799 AC: 6862 AN: 85908

European-Finnish (FIN) AF: 0.0724 AC: 3850 AN: 53192

Middle Eastern (MID) AF: 0.202 AC: 1160 AN: 5742

European-Non Finnish (NFE) AF: 0.223 AC: 245128 AN: 1100662

Other (OTH) AF: 0.178 AC: 10657 AN: 59926

GnomAD4 genome AF: 0.145 AC: 21994 AN: 152178 Hom.: 2141 Cov.: 32 AF XY: 0.136 AC XY: 10085 AN XY: 74422

African (AFR) AF: 0.0476 AC: 1977 AN: 41532

American (AMR) AF: 0.175 AC: 2683 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 830 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5176

South Asian (SAS) AF: 0.0740 AC: 357 AN: 4822

European-Finnish (FIN) AF: 0.0650 AC: 690 AN: 10612

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.217 AC: 14750 AN: 67972

Other (OTH) AF: 0.182 AC: 385 AN: 2110

Alfa AF: 0.183 Hom.: 947

Bravo AF: 0.150

Asia WGS AF: 0.0310 AC: 110 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Frontotemporal dementia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.7
DANN	Benign	0.69
PhyloP100		-0.60
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: rs75242405; hg19: chr17-44049329; COSMIC: COSV52248019; COSMIC: COSV52248019;