chr17-46027143-T-C

Position:

• chr17-46027143-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377265.1(MAPT):​c.*2972T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,328 control chromosomes in the GnomAD database, including 2,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2128 hom., cov: 32)
  • Exomes 𝑓: 0.091 (1 hom.)
• Consequence: MAPT NM_001377265.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.58

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-46027143-T-C is Benign according to our data. Variant chr17-46027143-T-C is described in ClinVar as [Benign]. Clinvar id is 323711.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/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.*2972T>C		3_prime_UTR_variant	13/13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.*2972T>C		3_prime_UTR_variant	13/13	1	NM_001377265.1	ENSP00000262410	A2
MAPT	ENST00000351559.10	c.*2972T>C		3_prime_UTR_variant	12/12	1		ENSP00000303214	A2
MAPT	ENST00000446361.7	c.*2972T>C		3_prime_UTR_variant	10/10	1		ENSP00000408975	P2

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21807 AN: 152144 Hom.: 2130 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.0650

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.0909 AC: 6 AN: 66 Hom.: 1 Cov.: 0 AF XY: 0.132 AC XY: 5 AN XY: 38

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.143 AC: 21796 AN: 152262 Hom.: 2128 Cov.: 32 AF XY: 0.134 AC XY: 9975 AN XY: 74444

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0738

Gnomad4 FIN AF: 0.0650

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.181

Alfa AF: 0.197 Hom.: 1497

Bravo AF: 0.148

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic intellectual disability Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

MAPT-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.18
DANN	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs17574228; hg19: chr17-44104509;