rs4523977

Positions:

• chr17-41727098-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_177977.3(HAP1):​c.1322C>T​(p.Thr441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,584,764 control chromosomes in the GnomAD database, including 43,780 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3108 hom., cov: 31)
  • Exomes 𝑓: 0.23 (40672 hom.)
• Consequence: HAP1 NM_177977.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.837

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025745928).
• BP6: Variant 17-41727098-G-A is Benign according to our data. Variant chr17-41727098-G-A is described in ClinVar as [Benign]. Clinvar id is 1242257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAP1	NM_177977.3	c.1322C>T	p.Thr441Met	missense_variant	9/11	ENST00000347901.9	NP_817084.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAP1	ENST00000347901.9	c.1322C>T	p.Thr441Met	missense_variant	9/11	1	NM_177977.3	ENSP00000334002
HAP1	ENST00000310778.5	c.1478C>T	p.Thr493Met	missense_variant	10/12	1		ENSP00000309392	P1
HAP1	ENST00000393939.6	c.1247C>T	p.Thr416Met	missense_variant	8/10	1		ENSP00000377513
HAP1	ENST00000341193.9	c.1271C>T	p.Thr424Met	missense_variant	8/10	2		ENSP00000343170

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27475 AN: 151976 Hom.: 3106 Cov.: 31

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.233 AC: 53177 AN: 227954 Hom.: 6597 AF XY: 0.241 AC XY: 29715 AN XY: 123120

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.214

Gnomad SAS exome AF: 0.340

Gnomad FIN exome AF: 0.268

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.232 AC: 332256 AN: 1432670 Hom.: 40672 Cov.: 28 AF XY: 0.236 AC XY: 168200 AN XY: 712494

Gnomad4 AFR exome AF: 0.0333

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.268

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.181 AC: 27471 AN: 152094 Hom.: 3108 Cov.: 31 AF XY: 0.186 AC XY: 13811 AN XY: 74340

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.347

Gnomad4 FIN AF: 0.269

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.189

Alfa AF: 0.217 Hom.: 7045

Bravo AF: 0.165

TwinsUK AF: 0.223 AC: 828

ALSPAC AF: 0.221 AC: 850

ESP6500AA AF: 0.0440 AC: 194

ESP6500EA AF: 0.220 AC: 1896

ExAC AF: 0.218 AC: 26419

Asia WGS AF: 0.252 AC: 877 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2021	This variant is associated with the following publications: (PMID: 22698993, 18192679) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

HAP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.28
DANN	Benign	0.57
DEOGEN2	Benign	0.063	.;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.60	T;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.14	.;.;.;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.012
Sift	Benign	0.65	T;T;T;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.44	B;B;B;B
Vest4		0.10
MPC		0.11
ClinPred		0.0010	T
GERP RS		-4.3
Varity_R		0.018
gMVP		0.046

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4523977; hg19: chr17-39883350; COSMIC: COSV57878024; COSMIC: COSV57878024;