rs34315806

Positions:

• chr4-3160307-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001388492.1(HTT):​c.3779C>T​(p.Thr1260Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00472 in 1,552,390 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (127 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (122 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 1.46

Genes affected

HTT (HGNC:4851): (huntingtin) Huntingtin is a disease gene linked to Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. This is thought to be caused by an expanded, unstable trinucleotide repeat in the huntingtin gene, which translates as a polyglutamine repeat in the protein product. A fairly broad range of trinucleotide repeats (9-35) has been identified in normal controls, and repeat numbers in excess of 40 have been described as pathological. The huntingtin locus is large, spanning 180 kb and consisting of 67 exons. The huntingtin gene is widely expressed and is required for normal development. It is expressed as 2 alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues. The larger transcript is approximately 13.7 kb and is expressed predominantly in adult and fetal brain whereas the smaller transcript of approximately 10.3 kb is more widely expressed. The genetic defect leading to Huntington's disease may not necessarily eliminate transcription, but may confer a new property on the mRNA or alter the function of the protein. One candidate is the huntingtin-associated protein-1, highly expressed in brain, which has increased affinity for huntingtin protein with expanded polyglutamine repeats. This gene contains an upstream open reading frame in the 5' UTR that inhibits expression of the huntingtin gene product through translational repression. [provided by RefSeq, Jul 2016]

HTT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HTT. . Gene score misZ 2.7799 (greater than the threshold 3.09). Trascript score misZ 3.7032 (greater than threshold 3.09). GenCC has associacion of gene with Lopes-Maciel-Rodan syndrome, Huntington disease, juvenile Huntington disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.002370596).
• BP6: Variant 4-3160307-C-T is Benign according to our data. Variant chr4-3160307-C-T is described in ClinVar as [Benign]. Clinvar id is 417743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.3779C>T	p.Thr1260Met	missense_variant	29/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.3779C>T	p.Thr1260Met	missense_variant	29/67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.3779C>T	p.Thr1260Met	missense_variant	29/67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3406 AN: 152154 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.0762

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00559 AC: 874 AN: 156426 Hom.: 35 AF XY: 0.00419 AC XY: 346 AN XY: 82626

Gnomad AFR exome AF: 0.0812

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000175

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000884

Gnomad OTH exome AF: 0.00433

GnomAD4 exome AF: 0.00280 AC: 3923 AN: 1400118 Hom.: 122 Cov.: 29 AF XY: 0.00254 AC XY: 1757 AN XY: 690612

Gnomad4 AFR exome AF: 0.0844

Gnomad4 AMR exome AF: 0.00607

Gnomad4 ASJ exome AF: 0.000238

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.000265

Gnomad4 FIN exome AF: 0.0000405

Gnomad4 NFE exome AF: 0.000527

Gnomad4 OTH exome AF: 0.00634

GnomAD4 genome AF: 0.0224 AC: 3411 AN: 152272 Hom.: 127 Cov.: 32 AF XY: 0.0216 AC XY: 1609 AN XY: 74460

Gnomad4 AFR AF: 0.0761

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00423 Hom.: 34

Bravo AF: 0.0264

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0635 AC: 245

ESP6500EA AF: 0.000980 AC: 8

ExAC AF: 0.00413 AC: 405

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2019	This variant is associated with the following publications: (PMID: 26740508) -

Lopes-Maciel-Rodan syndrome Pathogenic:1 Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_002111.6:c.3785C>T (p.Thr1262Met) was reported as T1260M in the literature. This variant has an allele frequency of 0.079 in African subpopulation in the gnomAD database, including 62 homozygous. Lopes et al. reported a patient with Rett syndrome-like phenotypes. WES revealed two compound heterozygous variants in the HTT gene: a maternal c.C2108T, p.(P703L) and a paternal c.C3779T, p.(T1260M). However, the author indictated the latter varaint T1260M as a polymorphism (PMID: 26740508). This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2, BS2. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 15, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.083, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.11
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.94	P
Vest4		0.19
MVP		0.70
MPC		0.55
ClinPred		0.031	T
GERP RS		-0.063
Varity_R		0.081
gMVP		0.32

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: rs34315806; hg19: chr4-3162034;