17-41727098-G-C

Variant names:

• chr17-41727098-G-C
• rs4523977
• NM_177977.3:c.1322C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177977.3(HAP1):​c.1322C>G​(p.Thr441Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T441M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HAP1 NM_177977.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.837
• Publications: 0 publications found

Genes affected

HAP1 (HGNC:4812): (huntingtin associated protein 1) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with huntingtin, with two cytoskeletal proteins (dynactin and pericentriolar autoantigen protein 1), and with a hepatocyte growth factor-regulated tyrosine kinase substrate. The interactions with cytoskeletal proteins and a kinase substrate suggest a role for this protein in vesicular trafficking or organelle transport. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08904803).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177977.3. 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
	HAP1	NM_177977.3	MANE Select	c.1322C>G	p.Thr441Arg	missense	Exon 9 of 11	NP_817084.2
	HAP1	NM_001367459.1		c.1418C>G	p.Thr473Arg	missense	Exon 9 of 12	NP_001354388.1
	HAP1	NM_001367460.1		c.1382C>G	p.Thr461Arg	missense	Exon 9 of 12	NP_001354389.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAP1	ENST00000347901.9	TSL:1 MANE Select	c.1322C>G	p.Thr441Arg	missense	Exon 9 of 11	ENSP00000334002.4
	HAP1	ENST00000310778.5	TSL:1	c.1478C>G	p.Thr493Arg	missense	Exon 10 of 12	ENSP00000309392.5
	HAP1	ENST00000393939.6	TSL:1	c.1247C>G	p.Thr416Arg	missense	Exon 8 of 10	ENSP00000377513.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438234 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 715120

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 42002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25702

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 84458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095812

Other (OTH) AF: 0.00 AC: 0 AN: 59570

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.87
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.84
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.067
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.22	T
Polyphen		0.98	D
Vest4		0.24
MutPred		0.36		Gain of MoRF binding (P = 0.0169)
MVP		0.21
MPC		0.12
ClinPred		0.19	T
GERP RS		-4.3
Varity_R		0.079
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4523977; hg19: chr17-39883350;