chr1-220880203-T-C

Variant names:

• chr1-220880203-T-C
• rs12141189
• NM_021958.4:c.346T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021958.4(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. 13/21 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: 𝑓 0.23 (4161 hom., cov: 33)
  • Exomes 𝑓: 0.24 (43156 hom.)
• Consequence: HLX NM_021958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 24 publications found

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]

ENSG00000286231 (HGNC:):

HLX-AS1 (HGNC:42509): (HLX antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021958.4. 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
	HLX	NM_021958.4	MANE Select	c.346T>C	p.Ser116Pro	missense	Exon 1 of 4	NP_068777.1	Q14774
	HLX-AS1	NR_046901.1		n.-63A>G		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLX	ENST00000366903.8	TSL:1 MANE Select	c.346T>C	p.Ser116Pro	missense	Exon 1 of 4	ENSP00000355870.5	Q14774
	ENSG00000286231	ENST00000651706.1		n.843-991T>C		intron	N/A	ENSP00000499157.1	A0A494C1P3
	HLX	ENST00000944514.1		c.346T>C	p.Ser116Pro	missense	Exon 1 of 4	ENSP00000614573.1

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

GnomAD2 exomes AF: 0.244 AC: 59203 AN: 242226 AF XY: 0.238

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 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

African (AFR) AF: 0.182 AC: 6078 AN: 33458

American (AMR) AF: 0.317 AC: 14159 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4581 AN: 26102

East Asian (EAS) AF: 0.195 AC: 7721 AN: 39680

South Asian (SAS) AF: 0.196 AC: 16920 AN: 86236

European-Finnish (FIN) AF: 0.306 AC: 16206 AN: 52892

Middle Eastern (MID) AF: 0.179 AC: 1028 AN: 5758

European-Non Finnish (NFE) AF: 0.243 AC: 270396 AN: 1111302

Other (OTH) AF: 0.229 AC: 13800 AN: 60228

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

African (AFR) AF: 0.188 AC: 7794 AN: 41492

American (AMR) AF: 0.256 AC: 3913 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 609 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1122 AN: 5152

South Asian (SAS) AF: 0.196 AC: 949 AN: 4830

European-Finnish (FIN) AF: 0.313 AC: 3310 AN: 10570

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16477 AN: 67978

Other (OTH) AF: 0.214 AC: 451 AN: 2108

Alfa AF: 0.241 Hom.: 7133

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 v4.9

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
PhyloP100		1.0
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
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

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