rs62621984

Variant names:

• chr1-220880232-A-C
• rs62621984
• NM_021958.4:c.375A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-220880232-A-C
• chr1-220880232-A-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_021958.4(HLX):​c.375A>C​(p.Gln125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 1,610,232 control chromosomes in the GnomAD database, including 1,277 homozygotes. 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: 𝑓 0.029 (84 hom., cov: 34)
  • Exomes 𝑓: 0.037 (1193 hom.)
• Consequence: HLX NM_021958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00100
• Publications: 10 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=0.0023978949).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0292 (4440/151802) while in subpopulation NFE AF = 0.0431 (2926/67954). AF 95% confidence interval is 0.0418. There are 84 homozygotes in GnomAd4. There are 2113 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 84 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLX	NM_021958.4	c.375A>C	p.Gln125His	missense_variant	Exon 1 of 4	ENST00000366903.8	NP_068777.1
HLX-AS1	NR_046901.1	n.-92T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLX	ENST00000366903.8	c.375A>C	p.Gln125His	missense_variant	Exon 1 of 4	1	NM_021958.4	ENSP00000355870.5
ENSG00000286231	ENST00000651706.1	n.843-962A>C		intron_variant	Intron 6 of 8			ENSP00000499157.1

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4441 AN: 151678 Hom.: 84 Cov.: 34

Gnomad AFR AF: 0.00761

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.0243

Gnomad EAS AF: 0.000395

Gnomad SAS AF: 0.00735

Gnomad FIN AF: 0.0388

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0430

Gnomad OTH AF: 0.0341

GnomAD2 exomes AF: 0.0311 AC: 7548 AN: 242920 AF XY: 0.0313

Gnomad AFR exome AF: 0.00701

Gnomad AMR exome AF: 0.0240

Gnomad ASJ exome AF: 0.0231

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.0372

Gnomad NFE exome AF: 0.0469

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.0366 AC: 53343 AN: 1458430 Hom.: 1193 Cov.: 33 AF XY: 0.0362 AC XY: 26262 AN XY: 725406

African (AFR) AF: 0.00562 AC: 188 AN: 33436

American (AMR) AF: 0.0242 AC: 1078 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.0218 AC: 568 AN: 26078

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39384

South Asian (SAS) AF: 0.00766 AC: 653 AN: 85278

European-Finnish (FIN) AF: 0.0403 AC: 2143 AN: 53210

Middle Eastern (MID) AF: 0.0388 AC: 223 AN: 5752

European-Non Finnish (NFE) AF: 0.0418 AC: 46447 AN: 1110512

Other (OTH) AF: 0.0339 AC: 2038 AN: 60162

GnomAD4 genome AF: 0.0292 AC: 4440 AN: 151802 Hom.: 84 Cov.: 34 AF XY: 0.0285 AC XY: 2113 AN XY: 74158

African (AFR) AF: 0.00756 AC: 314 AN: 41526

American (AMR) AF: 0.0360 AC: 549 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 84 AN: 3458

East Asian (EAS) AF: 0.000396 AC: 2 AN: 5056

South Asian (SAS) AF: 0.00757 AC: 35 AN: 4626

European-Finnish (FIN) AF: 0.0388 AC: 411 AN: 10606

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0431 AC: 2926 AN: 67954

Other (OTH) AF: 0.0333 AC: 70 AN: 2104

Alfa AF: 0.0401 Hom.: 112

Bravo AF: 0.0292

TwinsUK AF: 0.0278 AC: 103

ALSPAC AF: 0.0327 AC: 126

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0421 AC: 362

ExAC AF: 0.0312 AC: 3786

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0521

EpiControl AF: 0.0510

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.9
DANN	Benign	0.51
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.90	N
PhyloP100		-0.0010
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.087
Sift	Benign	0.047	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.88	P
Vest4		0.36
MutPred		0.16		Loss of helix (P = 0.1299);
MPC		0.43
ClinPred		0.022	T
GERP RS		-0.054
Varity_R		0.047
gMVP		0.50
Mutation Taster		=99/1	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: rs62621984; hg19: chr1-221053574; COSMIC: COSV65044417; COSMIC: COSV65044417;