rs2276881

chr4-3229934-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001388492.1(HTT):c.8157G>A(p.Leu2719=) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.086 in 1,613,994 control chromosomes in the GnomAD database, including 8,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.075 (839 hom., cov: 33)
  • Exomes 𝑓: 0.087 (8155 hom.)
• Consequence: HTT NM_001388492.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.13

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 4-3229934-G-A is Benign according to our data. Variant chr4-3229934-G-A is described in ClinVar as [Benign]. Clinvar id is 2167059.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-3229934-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.8157G>A	p.Leu2719=	synonymous_variant	60/67	ENST00000355072.11
HTT	NM_002111.8	c.8163G>A	p.Leu2721=	synonymous_variant	60/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.8157G>A	p.Leu2719=	synonymous_variant	60/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.0755 AC: 11489 AN: 152184 Hom.: 838 Cov.: 33

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.0660

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.0458

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.0907

GnomAD3 exomes AF: 0.114 AC: 28321 AN: 249270 Hom.: 2579 AF XY: 0.112 AC XY: 15118 AN XY: 135268

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.0671

Gnomad EAS exome AF: 0.336

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0692

Gnomad OTH exome AF: 0.0931

GnomAD4 exome AF: 0.0871 AC: 127375 AN: 1461692 Hom.: 8155 Cov.: 32 AF XY: 0.0885 AC XY: 64362 AN XY: 727180

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.0633

Gnomad4 EAS exome AF: 0.354

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.0507

Gnomad4 NFE exome AF: 0.0715

Gnomad4 OTH exome AF: 0.0958

GnomAD4 genome AF: 0.0754 AC: 11490 AN: 152302 Hom.: 839 Cov.: 33 AF XY: 0.0794 AC XY: 5914 AN XY: 74450

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.0660

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.0458

Gnomad4 NFE AF: 0.0709

Gnomad4 OTH AF: 0.0888

Alfa AF: 0.0719 Hom.: 781

Bravo AF: 0.0814

Asia WGS AF: 0.208 AC: 723 AN: 3478

EpiCase AF: 0.0711

EpiControl AF: 0.0666

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	10
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2276881; hg19: chr4-3231661; COSMIC: COSV61871670; COSMIC: COSV61871670;