rs362331

chr4-3214108-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_001388492.1(HTT):c.6925T>C(p.Tyr2309His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,568,922 control chromosomes in the GnomAD database, including 146,149 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (17425 hom., cov: 32)
  • Exomes 𝑓: 0.42 (128724 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.22

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.

• PP2: Missense variant where missense usually causes diseases, HTT
• BP4: Computational evidence support a benign effect (MetaRNN=1.4734268E-4).
• BP6: Variant 4-3214108-T-C is Benign according to our data. Variant chr4-3214108-T-C is described in ClinVar as [Benign]. Clinvar id is 1559386.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-3214108-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTT	NM_001388492.1	c.6925T>C	p.Tyr2309His	missense_variant	50/67	ENST00000355072.11
HTT	NM_002111.8	c.6931T>C	p.Tyr2311His	missense_variant	50/67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTT	ENST00000355072.11	c.6925T>C	p.Tyr2309His	missense_variant	50/67	1	NM_001388492.1	P2

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71325 AN: 151946 Hom.: 17389 Cov.: 32

Gnomad AFR AF: 0.585

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.429 AC: 97562 AN: 227262 Hom.: 21568 AF XY: 0.421 AC XY: 52199 AN XY: 123886

Gnomad AFR exome AF: 0.582

Gnomad AMR exome AF: 0.380

Gnomad ASJ exome AF: 0.496

Gnomad EAS exome AF: 0.430

Gnomad SAS exome AF: 0.315

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.424 AC: 600684 AN: 1416858 Hom.: 128724 Cov.: 35 AF XY: 0.420 AC XY: 295062 AN XY: 702384

Gnomad4 AFR exome AF: 0.590

Gnomad4 AMR exome AF: 0.376

Gnomad4 ASJ exome AF: 0.502

Gnomad4 EAS exome AF: 0.414

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.537

Gnomad4 NFE exome AF: 0.422

Gnomad4 OTH exome AF: 0.431

GnomAD4 genome AF: 0.470 AC: 71410 AN: 152064 Hom.: 17425 Cov.: 32 AF XY: 0.467 AC XY: 34725 AN XY: 74360

Gnomad4 AFR AF: 0.585

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.506

Gnomad4 EAS AF: 0.420

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.423

Gnomad4 OTH AF: 0.421

Alfa AF: 0.425 Hom.: 32109

Bravo AF: 0.464

TwinsUK AF: 0.409 AC: 1518

ALSPAC AF: 0.423 AC: 1629

ESP6500AA AF: 0.565 AC: 2355

ESP6500EA AF: 0.420 AC: 3533

ExAC AF: 0.427 AC: 51670

Asia WGS AF: 0.419 AC: 1458 AN: 3478

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.00015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.18
Sift	Benign	0.69	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.49
ClinPred		0.0063	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.026
gMVP		0.39

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: rs362331; hg19: chr4-3215835; COSMIC: COSV61860651; COSMIC: COSV61860651;