rs4690072

Variant names:

• chr4-3120780-T-G
• rs4690072
• NM_001388492.1:c.1069-448T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001388492.1(HTT):​c.1069-448T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 152,118 control chromosomes in the GnomAD database, including 17,467 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (17467 hom., cov: 32)
• Consequence: HTT NM_001388492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.1069-448T>G		intron_variant	Intron 8 of 66	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.1069-448T>G		intron_variant	Intron 8 of 66		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.1069-448T>G		intron_variant	Intron 8 of 66	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71487 AN: 152000 Hom.: 17426 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.416

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.471 AC: 71576 AN: 152118 Hom.: 17467 Cov.: 32 AF XY: 0.468 AC XY: 34792 AN XY: 74368

African (AFR) AF: 0.584 AC: 24221 AN: 41478

American (AMR) AF: 0.394 AC: 6035 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1777 AN: 3468

East Asian (EAS) AF: 0.430 AC: 2228 AN: 5178

South Asian (SAS) AF: 0.304 AC: 1466 AN: 4826

European-Finnish (FIN) AF: 0.554 AC: 5857 AN: 10566

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28702 AN: 67988

Other (OTH) AF: 0.421 AC: 889 AN: 2114

Alfa AF: 0.466 Hom.: 2187

Bravo AF: 0.466

Asia WGS AF: 0.423 AC: 1470 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.8
DANN	Benign	0.77
PhyloP100		-1.5
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: rs4690072; hg19: chr4-3122507;