rs34315806

Variant names:

• chr4-3160307-C-T
• rs34315806
• NM_001388492.1:c.3779C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000355072.11(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. 14/21 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 ENST00000355072.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 1.46
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• Huntington disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• Lopes-Maciel-Rodan syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• juvenile Huntington disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355072.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.3779C>T	p.Thr1260Met	missense	Exon 29 of 67	NP_001375421.1
	HTT	NM_002111.8		c.3779C>T	p.Thr1260Met	missense	Exon 29 of 67	NP_002102.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	ENST00000355072.11	TSL:1 MANE Select	c.3779C>T	p.Thr1260Met	missense	Exon 29 of 67	ENSP00000347184.5
	HTT	ENST00000510626.5	TSL:1	n.3878C>T		non_coding_transcript_exon	Exon 16 of 53
	HTT	ENST00000681528.1		c.3521C>T	p.Thr1174Met	missense	Exon 29 of 68	ENSP00000506116.1

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

GnomAD2 exomes AF: 0.00559 AC: 874 AN: 156426 AF XY: 0.00419

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 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

African (AFR) AF: 0.0844 AC: 2681 AN: 31760

American (AMR) AF: 0.00607 AC: 217 AN: 35744

Ashkenazi Jewish (ASJ) AF: 0.000238 AC: 6 AN: 25182

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 36020

South Asian (SAS) AF: 0.000265 AC: 21 AN: 79276

European-Finnish (FIN) AF: 0.0000405 AC: 2 AN: 49358

Middle Eastern (MID) AF: 0.0102 AC: 58 AN: 5696

European-Non Finnish (NFE) AF: 0.000527 AC: 569 AN: 1079044

Other (OTH) AF: 0.00634 AC: 368 AN: 58038

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

African (AFR) AF: 0.0761 AC: 3159 AN: 41518

American (AMR) AF: 0.0105 AC: 160 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68034

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.00747 Hom.: 136

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
1	-	1	Lopes-Maciel-Rodan syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.5
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
PromoterAI		0.027	Neutral
Varity_R		0.081
gMVP		0.32
Mutation Taster		=97/3	disease causing (ClinVar)

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: rs34315806; hg19: chr4-3162034;