rs768047421

Variant names:

• chr4-3131647-C-T
• rs768047421
• NM_001388492.1:c.2108C>T
• HTT p.Pro703Leu

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS1

The NM_001388492.1(HTT):​c.2108C>T​(p.Pro703Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,612,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 5.70
• Publications: 3 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: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000431 (63/1460470) while in subpopulation MID AF = 0.000532 (3/5640). AF 95% confidence interval is 0.000144. There are 0 homozygotes in GnomAdExome4. There are 41 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388492.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	NM_001388492.1	MANE Select	c.2108C>T	p.Pro703Leu	missense	Exon 16 of 67	NP_001375421.1	P42858
	HTT	NM_002111.8		c.2108C>T	p.Pro703Leu	missense	Exon 16 of 67	NP_002102.4	P42858

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTT	ENST00000355072.11	TSL:1 MANE Select	c.2108C>T	p.Pro703Leu	missense	Exon 16 of 67	ENSP00000347184.5	P42858
	HTT	ENST00000510626.5	TSL:1	n.2207C>T		non_coding_transcript_exon	Exon 3 of 53
	HTT	ENST00000681528.1		c.1850C>T	p.Pro617Leu	missense	Exon 16 of 68	ENSP00000506116.1	A0A7P0TAC5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000806 AC: 20 AN: 248284 AF XY: 0.000104

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.000701

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1460470 Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41 AN XY: 726420

African (AFR) AF: 0.0000599 AC: 2 AN: 33412

American (AMR) AF: 0.0000225 AC: 1 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.000921 AC: 24 AN: 26066

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000532 AC: 3 AN: 5640

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111358

Other (OTH) AF: 0.0000829 AC: 5 AN: 60322

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74294

African (AFR) AF: 0.0000242 AC: 1 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000756

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Huntington disease (1)
1	-	-	Lopes-Maciel-Rodan syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.56
Mutation Taster		=75/25	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs768047421;

hg19: chr4-3133374;

COSMIC: COSV61869483;