4-3074876-CCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-CCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr4-3074876-CCAGCAGCAGCAGCAGCAG-C
• rs71180116
• NM_001388492.1:c.93_110delGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_001388492.1(HTT):​c.93_110delGCAGCAGCAGCAGCAGCA​(p.Gln32_Gln37del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000852 in 1,357,712 control chromosomes in the GnomAD database, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00079 (2 hom.)
• Consequence: HTT NM_001388492.1 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.65
• Publications: 6 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001388492.1
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00144 (190/131876) while in subpopulation SAS AF = 0.00409 (16/3910). AF 95% confidence interval is 0.00257. There are 1 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1	c.93_110delGCAGCAGCAGCAGCAGCA	p.Gln32_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.93_110delGCAGCAGCAGCAGCAGCA	p.Gln32_Gln37del	disruptive_inframe_deletion	Exon 1 of 67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.93_110delGCAGCAGCAGCAGCAGCA	p.Gln32_Gln37del	disruptive_inframe_deletion	Exon 1 of 67	1	NM_001388492.1	ENSP00000347184.5

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 185 AN: 131778 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00358

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000520

Gnomad OTH AF: 0.00445

GnomAD4 exome AF: 0.000789 AC: 967 AN: 1225836 Hom.: 2 AF XY: 0.000801 AC XY: 487 AN XY: 608130

African (AFR) AF: 0.00353 AC: 91 AN: 25812

American (AMR) AF: 0.00195 AC: 59 AN: 30300

Ashkenazi Jewish (ASJ) AF: 0.000176 AC: 4 AN: 22734

East Asian (EAS) AF: 0.000619 AC: 18 AN: 29096

South Asian (SAS) AF: 0.00222 AC: 160 AN: 72222

European-Finnish (FIN) AF: 0.000185 AC: 6 AN: 32500

Middle Eastern (MID) AF: 0.000529 AC: 2 AN: 3784

European-Non Finnish (NFE) AF: 0.000597 AC: 572 AN: 957550

Other (OTH) AF: 0.00106 AC: 55 AN: 51838

GnomAD4 genome AF: 0.00144 AC: 190 AN: 131876 Hom.: 1 Cov.: 0 AF XY: 0.00167 AC XY: 106 AN XY: 63422

African (AFR) AF: 0.00282 AC: 100 AN: 35516

American (AMR) AF: 0.00186 AC: 25 AN: 13412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3190

East Asian (EAS) AF: 0.00194 AC: 8 AN: 4124

South Asian (SAS) AF: 0.00409 AC: 16 AN: 3910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.000520 AC: 32 AN: 61488

Other (OTH) AF: 0.00496 AC: 9 AN: 1816

Alfa AF: 0.00 Hom.: 452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=125/75	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs71180116; hg19: chr4-3076603;