ENST00000681528.1:c.5+13837A>G

Variant names:

• chr4-3056082-A-G
• rs1313770
• ENST00000660368.2:n.1449+6352T>C

Variant summary

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

The ENST00000681528.1(HTT):​c.5+13837A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 152,078 control chromosomes in the GnomAD database, including 25,070 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 0.57 (25070 hom., cov: 32)
• Consequence: HTT ENST00000681528.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.875
• Publications: 4 publications found

Genes affected

HTT-AS (HGNC:37118): (HTT antisense RNA)

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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Lopes-Maciel-Rodan syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000681528.1. 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
	HTT-AS	NR_185914.2	MANE Select	n.1449+6352T>C		intron	N/A
	HTT-AS	NR_045414.2		n.1662+6352T>C		intron	N/A
	HTT-AS	NR_185915.1		n.1466+6352T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT-AS	ENST00000660368.2	MANE Select	n.1449+6352T>C		intron	N/A
	HTT	ENST00000681528.1		c.5+13837A>G		intron	N/A	ENSP00000506116.1	A0A7P0TAC5
	HTT	ENST00000680956.1		c.5+13837A>G		intron	N/A	ENSP00000506029.1	A0A7P0TA78

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86506 AN: 151960 Hom.: 25028 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.600

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

GnomAD4 genome AF: 0.569 AC: 86600 AN: 152078 Hom.: 25070 Cov.: 32 AF XY: 0.568 AC XY: 42246 AN XY: 74340

African (AFR) AF: 0.637 AC: 26436 AN: 41476

American (AMR) AF: 0.604 AC: 9224 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1986 AN: 3468

East Asian (EAS) AF: 0.415 AC: 2148 AN: 5170

South Asian (SAS) AF: 0.733 AC: 3536 AN: 4826

European-Finnish (FIN) AF: 0.417 AC: 4410 AN: 10570

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.543 AC: 36905 AN: 67976

Other (OTH) AF: 0.597 AC: 1261 AN: 2112

Alfa AF: 0.543 Hom.: 2688

Bravo AF: 0.580

Asia WGS AF: 0.532 AC: 1849 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.3
DANN	Benign	0.56
PhyloP100		-0.88

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1313770; hg19: chr4-3057809;