rs363125

Variant names:

• chr4-3187820-C-A
• rs363125
• NM_001388492.1:c.5159C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3187820-C-A
• chr4-3187820-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_001388492.1(HTT):​c.5159C>A​(p.Thr1720Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,611,318 control chromosomes in the GnomAD database, including 16,012 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1720S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (4433 hom., cov: 32)
  • Exomes 𝑓: 0.11 (11579 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50
• Publications: 22 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=4.3118E-4).
• BP6: Variant 4-3187820-C-A is Benign according to our data. Variant chr4-3187820-C-A is described in ClinVar as Benign. ClinVar VariationId is 1538968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.5159C>A	p.Thr1720Asn	missense_variant	Exon 39 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.5159C>A	p.Thr1720Asn	missense_variant	Exon 39 of 67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.5159C>A	p.Thr1720Asn	missense_variant	Exon 39 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29494 AN: 151990 Hom.: 4408 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00712

Gnomad SAS AF: 0.0993

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.119 AC: 29785 AN: 249434 AF XY: 0.117

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.0739

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.00656

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.111 AC: 162432 AN: 1459210 Hom.: 11579 Cov.: 30 AF XY: 0.110 AC XY: 80088 AN XY: 726110

African (AFR) AF: 0.442 AC: 14741 AN: 33334

American (AMR) AF: 0.0770 AC: 3444 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4724 AN: 26096

East Asian (EAS) AF: 0.00572 AC: 227 AN: 39696

South Asian (SAS) AF: 0.0983 AC: 8474 AN: 86188

European-Finnish (FIN) AF: 0.106 AC: 5683 AN: 53404

Middle Eastern (MID) AF: 0.223 AC: 1286 AN: 5758

European-Non Finnish (NFE) AF: 0.104 AC: 115966 AN: 1109730

Other (OTH) AF: 0.131 AC: 7887 AN: 60302

GnomAD4 genome AF: 0.194 AC: 29560 AN: 152108 Hom.: 4433 Cov.: 32 AF XY: 0.190 AC XY: 14150 AN XY: 74346

African (AFR) AF: 0.425 AC: 17611 AN: 41438

American (AMR) AF: 0.113 AC: 1724 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 629 AN: 3466

East Asian (EAS) AF: 0.00714 AC: 37 AN: 5184

South Asian (SAS) AF: 0.0988 AC: 476 AN: 4820

European-Finnish (FIN) AF: 0.108 AC: 1139 AN: 10592

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7436 AN: 68006

Other (OTH) AF: 0.177 AC: 374 AN: 2114

Alfa AF: 0.134 Hom.: 8173

Bravo AF: 0.204

TwinsUK AF: 0.0995 AC: 369

ALSPAC AF: 0.107 AC: 414

ESP6500AA AF: 0.402 AC: 1484

ESP6500EA AF: 0.117 AC: 960

ExAC AF: 0.127 AC: 15306

Asia WGS AF: 0.0940 AC: 325 AN: 3478

EpiCase AF: 0.104

EpiControl AF: 0.116

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0040
DANN	Benign	0.22
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.053	T
MetaRNN	Benign	0.00043	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.5
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.021
Sift	Benign	0.96	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.43
ClinPred		0.016	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.11
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: rs363125; hg19: chr4-3189547; COSMIC: COSV61859837;