rs754481229

Variant names:

• chr4-3074926-AGCAG-A
• rs754481229
• NM_001388492.1:c.102_105delGCAG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BS1 BS2

The NM_002111.8(HTT):​c.102_105delGCAG​(p.Gln34HisfsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 141,172 control chromosomes in the GnomAD database, including 36 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.016 (36 hom., cov: 25)
  • Exomes 𝑓: 0.011 (249 hom.)
  • Failed GnomAD Quality Control
• Consequence: HTT NM_002111.8 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.80
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 4-3074926-AGCAG-A is Benign according to our data. Variant chr4-3074926-AGCAG-A is described in ClinVar as Benign. ClinVar VariationId is 402953.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0161 (2277/141172) while in subpopulation NFE AF = 0.0237 (1528/64438). AF 95% confidence interval is 0.0227. There are 36 homozygotes in GnomAd4. There are 1027 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002111.8. 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.102_105delGCAG	p.Gln34HisfsTer66	frameshift	Exon 1 of 67	NP_001375421.1
	HTT	NM_002111.8		c.102_105delGCAG	p.Gln34HisfsTer66	frameshift	Exon 1 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.102_105delGCAG	p.Gln34HisfsTer66	frameshift	Exon 1 of 67	ENSP00000347184.5
	HTT	ENST00000681528.1		c.6-12012_6-12009delGCAG		intron	N/A	ENSP00000506116.1
	HTT	ENST00000680956.1		c.6-12012_6-12009delGCAG		intron	N/A	ENSP00000506029.1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2281 AN: 141102 Hom.: 36 Cov.: 25

Gnomad AFR AF: 0.00520

Gnomad AMI AF: 0.0108

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.0362

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.00741 AC: 728 AN: 98246 AF XY: 0.00762

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00883

Gnomad OTH exome AF: 0.00997

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0113 AC: 15025 AN: 1325628 Hom.: 249 AF XY: 0.0115 AC XY: 7510 AN XY: 653424

African (AFR) AF: 0.00323 AC: 87 AN: 26944

American (AMR) AF: 0.00590 AC: 194 AN: 32870

Ashkenazi Jewish (ASJ) AF: 0.0370 AC: 870 AN: 23540

East Asian (EAS) AF: 0.00 AC: 0 AN: 31344

South Asian (SAS) AF: 0.00624 AC: 466 AN: 74672

European-Finnish (FIN) AF: 0.00720 AC: 245 AN: 34050

Middle Eastern (MID) AF: 0.0284 AC: 114 AN: 4014

European-Non Finnish (NFE) AF: 0.0118 AC: 12315 AN: 1043258

Other (OTH) AF: 0.0134 AC: 734 AN: 54936

GnomAD4 genome AF: 0.0161 AC: 2277 AN: 141172 Hom.: 36 Cov.: 25 AF XY: 0.0149 AC XY: 1027 AN XY: 68954

African (AFR) AF: 0.00521 AC: 193 AN: 37028

American (AMR) AF: 0.0131 AC: 190 AN: 14526

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 209 AN: 3310

East Asian (EAS) AF: 0.00 AC: 0 AN: 4824

South Asian (SAS) AF: 0.0104 AC: 47 AN: 4516

European-Finnish (FIN) AF: 0.00518 AC: 49 AN: 9452

Middle Eastern (MID) AF: 0.0355 AC: 10 AN: 282

European-Non Finnish (NFE) AF: 0.0237 AC: 1528 AN: 64438

Other (OTH) AF: 0.0214 AC: 42 AN: 1960

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=187/13	disease causing (fs/PTC)

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: rs754481229; hg19: chr4-3076653;