chr1-220880203-T-C

Position:

• chr1-220880203-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000366903.8(HLX):​c.346T>C​(p.Ser116Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,612,368 control chromosomes in the GnomAD database, including 47,317 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (4161 hom., cov: 33)
  • Exomes 𝑓: 0.24 (43156 hom.)
• Consequence: HLX ENST00000366903.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

Genes affected

HLX (HGNC:4978): (H2.0 like homeobox) Enables sequence-specific DNA binding activity. Predicted to be involved in cell differentiation and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including animal organ development; enteric nervous system development; and regulation of T-helper cell differentiation. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001368612).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLX	NM_021958.4	c.346T>C	p.Ser116Pro	missense_variant	1/4	ENST00000366903.8	NP_068777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLX	ENST00000366903.8	c.346T>C	p.Ser116Pro	missense_variant	1/4	1	NM_021958.4	ENSP00000355870	P1
HLX	ENST00000549319.2	n.773T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34929 AN: 151988 Hom.: 4153 Cov.: 33

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.244 AC: 59203 AN: 242226 Hom.: 7632 AF XY: 0.238 AC XY: 31515 AN XY: 132336

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.229

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.240 AC: 350889 AN: 1460262 Hom.: 43156 Cov.: 35 AF XY: 0.238 AC XY: 172835 AN XY: 726452

Gnomad4 AFR exome AF: 0.182

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.195

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.229

GnomAD4 genome AF: 0.230 AC: 34958 AN: 152106 Hom.: 4161 Cov.: 33 AF XY: 0.234 AC XY: 17369 AN XY: 74358

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.214

Alfa AF: 0.231 Hom.: 1799

Bravo AF: 0.226

ESP6500AA AF: 0.193 AC: 846

ESP6500EA AF: 0.222 AC: 1904

ExAC AF: 0.233 AC: 28129

Asia WGS AF: 0.184 AC: 639 AN: 3472

EpiCase AF: 0.230

EpiControl AF: 0.227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.18	P
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.028
Sift	Benign	0.086	T
Sift4G	Benign	0.36	T
Polyphen		0.048	B
Vest4		0.065
MPC		0.58
ClinPred		0.0053	T
GERP RS		3.4
Varity_R		0.25
gMVP		0.47

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: rs12141189; hg19: chr1-221053545; COSMIC: COSV65044290; COSMIC: COSV65044290;