4-3215088-C-G

Variant names:

• chr4-3215088-C-G
• rs916171
• NM_001388492.1:c.6953-22C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000355072.11(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16911 hom., cov: 32)
  • Exomes 𝑓: 0.42 (124727 hom.)
• Consequence: HTT ENST00000355072.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355072.11. 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.6953-22C>G		intron	N/A	NP_001375421.1
	HTT	NM_002111.8		c.6953-22C>G		intron	N/A	NP_002102.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	ENST00000355072.11	TSL:1 MANE Select	c.6953-22C>G		intron	N/A	ENSP00000347184.5
	HTT	ENST00000510626.5	TSL:1	n.8081-22C>G		intron	N/A
	HTT	ENST00000681528.1		c.6785-22C>G		intron	N/A	ENSP00000506116.1

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

GnomAD2 exomes AF: 0.418 AC: 101724 AN: 243544 AF XY: 0.409

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 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

African (AFR) AF: 0.580 AC: 18934 AN: 32620

American (AMR) AF: 0.364 AC: 15936 AN: 43824

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 12399 AN: 25806

East Asian (EAS) AF: 0.409 AC: 16154 AN: 39482

South Asian (SAS) AF: 0.291 AC: 24602 AN: 84642

European-Finnish (FIN) AF: 0.533 AC: 28389 AN: 53248

Middle Eastern (MID) AF: 0.354 AC: 2002 AN: 5656

European-Non Finnish (NFE) AF: 0.415 AC: 447337 AN: 1078068

Other (OTH) AF: 0.420 AC: 24789 AN: 59042

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

African (AFR) AF: 0.578 AC: 23972 AN: 41444

American (AMR) AF: 0.375 AC: 5729 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1692 AN: 3468

East Asian (EAS) AF: 0.415 AC: 2140 AN: 5162

South Asian (SAS) AF: 0.293 AC: 1412 AN: 4818

European-Finnish (FIN) AF: 0.548 AC: 5795 AN: 10568

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.416 AC: 28301 AN: 67954

Other (OTH) AF: 0.406 AC: 855 AN: 2104

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.45
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs916171; hg19: chr4-3216815;