rs73314997

Variant names:

• chr17-45983757-C-T
• rs73314997
• NM_001377265.1:c.1178C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-45983757-C-T
• chr17-45983757-C-G

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.1178C>T​(p.Ser393Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0105 in 1,614,056 control chromosomes in the GnomAD database, including 1,325 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S393S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.052 (715 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (610 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.83
• Publications: 20 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 (MetaRNN=0.0020686686).
• BP6: Variant 17-45983757-C-T is Benign according to our data. Variant chr17-45983757-C-T is described in ClinVar as Benign. ClinVar VariationId is 257505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 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.1178C>T	p.Ser393Leu	missense	Exon 5 of 13	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.953C>T	p.Ser318Leu	missense	Exon 6 of 15	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.953C>T	p.Ser318Leu	missense	Exon 6 of 14	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.1178C>T	p.Ser393Leu	missense	Exon 5 of 13	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.1178C>T	p.Ser393Leu	missense	Exon 5 of 11	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.374-3283C>T		intron	N/A	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes AF: 0.0517 AC: 7872 AN: 152138 Hom.: 711 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0382

GnomAD2 exomes AF: 0.0143 AC: 3573 AN: 250466 AF XY: 0.0109

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.00950

GnomAD4 exome AF: 0.00614 AC: 8969 AN: 1461800 Hom.: 610 Cov.: 35 AF XY: 0.00546 AC XY: 3971 AN XY: 727202

African (AFR) AF: 0.184 AC: 6148 AN: 33480

American (AMR) AF: 0.0121 AC: 539 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86258

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53354

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5768

European-Non Finnish (NFE) AF: 0.00115 AC: 1281 AN: 1111990

Other (OTH) AF: 0.0139 AC: 838 AN: 60396

GnomAD4 genome AF: 0.0519 AC: 7898 AN: 152256 Hom.: 715 Cov.: 33 AF XY: 0.0496 AC XY: 3690 AN XY: 74458

African (AFR) AF: 0.178 AC: 7408 AN: 41536

American (AMR) AF: 0.0199 AC: 304 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 68012

Other (OTH) AF: 0.0378 AC: 80 AN: 2114

Alfa AF: 0.0179 Hom.: 419

Bravo AF: 0.0590

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.172 AC: 759

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.0171 AC: 2082

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Frontotemporal dementia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.046
Sift	Benign	0.19	T
Sift4G	Benign	0.38	T
Polyphen		0.26	B
Vest4		0.23
MPC		0.13
ClinPred		0.020	T
GERP RS		4.4
Varity_R		0.076
gMVP		0.15
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: rs73314997; hg19: chr17-44061123; COSMIC: COSV52242297; COSMIC: COSV52242297;