rs916171

Positions:

• chr4-3215088-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001388492.1(HTT):​c.6953-22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 1,574,388 control chromosomes in the GnomAD database, including 141,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.46 (16911 hom., cov: 32)
  • Exomes 𝑓: 0.42 (124727 hom.)
• Consequence: HTT NM_001388492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-3215088-C-G is Benign according to our data. Variant chr4-3215088-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.6953-22C>G		intron_variant		ENST00000355072.11
HTT	NM_002111.8	c.6953-22C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.6953-22C>G		intron_variant		1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70202 AN: 151882 Hom.: 16878 Cov.: 32

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.402

GnomAD3 exomes AF: 0.418 AC: 101724 AN: 243544 Hom.: 21890 AF XY: 0.409 AC XY: 54068 AN XY: 132090

Gnomad AFR exome AF: 0.574

Gnomad AMR exome AF: 0.369

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.422

Gnomad SAS exome AF: 0.296

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.415 AC: 590542 AN: 1422388 Hom.: 124727 Cov.: 23 AF XY: 0.410 AC XY: 291240 AN XY: 709592

Gnomad4 AFR exome AF: 0.580

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.480

Gnomad4 EAS exome AF: 0.409

Gnomad4 SAS exome AF: 0.291

Gnomad4 FIN exome AF: 0.533

Gnomad4 NFE exome AF: 0.415

Gnomad4 OTH exome AF: 0.420

GnomAD4 genome AF: 0.462 AC: 70281 AN: 152000 Hom.: 16911 Cov.: 32 AF XY: 0.460 AC XY: 34151 AN XY: 74308

Gnomad4 AFR AF: 0.578

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.548

Gnomad4 NFE AF: 0.416

Gnomad4 OTH AF: 0.406

Alfa AF: 0.443 Hom.: 2801

Bravo AF: 0.456

Asia WGS AF: 0.414 AC: 1441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs916171; hg19: chr4-3216815;