rs7685686

Positions:

• chr4-3205415-A-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.5719-1081A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 151,958 control chromosomes in the GnomAD database, including 19,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.49 (19440 hom., cov: 33)
• Consequence: HTT NM_001388492.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153

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=-0.97).
• BP6: Variant 4-3205415-A-G is Benign according to our data. Variant chr4-3205415-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.5719-1081A>G		intron_variant		ENST00000355072.11
HTT	NM_002111.8	c.5719-1081A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.5719-1081A>G		intron_variant		1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74571 AN: 151840 Hom.: 19398 Cov.: 33

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.439

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

GnomAD4 genome AF: 0.491 AC: 74664 AN: 151958 Hom.: 19440 Cov.: 33 AF XY: 0.488 AC XY: 36208 AN XY: 74238

Gnomad4 AFR AF: 0.661

Gnomad4 AMR AF: 0.395

Gnomad4 ASJ AF: 0.509

Gnomad4 EAS AF: 0.404

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.423

Gnomad4 OTH AF: 0.443

Alfa AF: 0.426 Hom.: 16778

Bravo AF: 0.490

Asia WGS AF: 0.415 AC: 1437 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.4
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs7685686; hg19: chr4-3207142;