4-3148053-C-A

Position:

• chr4-3148053-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2 PP2 BP4_Strong BS1

The NM_001388492.1(HTT):​c.3344C>A​(p.Ala1115Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HTT NM_001388492.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HTT. . Gene score misZ 2.7799 (greater than the threshold 3.09). Trascript score misZ 3.7032 (greater than threshold 3.09). GenCC has associacion of gene with Lopes-Maciel-Rodan syndrome, Huntington disease, juvenile Huntington disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.05509901).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00000205 (3/1461764) while in subpopulation SAS AF= 0.0000348 (3/86244). AF 95% confidence interval is 0.00000924. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTT	NM_001388492.1	c.3344C>A	p.Ala1115Asp	missense_variant	26/67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8	c.3350C>A	p.Ala1117Asp	missense_variant	26/67		NP_002102.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11	c.3344C>A	p.Ala1115Asp	missense_variant	26/67	1	NM_001388492.1	ENSP00000347184	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249370 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461764 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.014
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.21	B
Vest4		0.31
MutPred		0.17		Loss of glycosylation at P1117 (P = 0.0287);
MVP		0.23
MPC		0.64
ClinPred		0.23	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1065747; hg19: chr4-3149780;