chr1-220884397-C-G

Variant names:

• chr1-220884397-C-G
• rs11578466
• NM_021958.4:c.1160C>G

Variant summary

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

The NM_021958.4(HLX):​c.1160C>G​(p.Ala387Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,613,906 control chromosomes in the GnomAD database, including 15,283 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 0.12 (1211 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14072 hom.)
• Consequence: HLX NM_021958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.504
• Publications: 20 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:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012665093).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLX	NM_021958.4	c.1160C>G	p.Ala387Gly	missense_variant	Exon 4 of 4	ENST00000366903.8	NP_068777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLX	ENST00000366903.8	c.1160C>G	p.Ala387Gly	missense_variant	Exon 4 of 4	1	NM_021958.4	ENSP00000355870.5
ENSG00000286231	ENST00000651706.1	n.*468C>G		non_coding_transcript_exon_variant	Exon 9 of 9			ENSP00000499157.1
ENSG00000286231	ENST00000651706.1	n.*468C>G		3_prime_UTR_variant	Exon 9 of 9			ENSP00000499157.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17975 AN: 152014 Hom.: 1212 Cov.: 32

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.119 AC: 29826 AN: 249994 AF XY: 0.121

Gnomad AFR exome AF: 0.0766

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.132 AC: 192697 AN: 1461774 Hom.: 14072 Cov.: 33 AF XY: 0.131 AC XY: 95398 AN XY: 727186

African (AFR) AF: 0.0808 AC: 2706 AN: 33480

American (AMR) AF: 0.113 AC: 5074 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5633 AN: 26132

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39700

South Asian (SAS) AF: 0.0674 AC: 5811 AN: 86254

European-Finnish (FIN) AF: 0.114 AC: 6075 AN: 53406

Middle Eastern (MID) AF: 0.262 AC: 1511 AN: 5766

European-Non Finnish (NFE) AF: 0.142 AC: 157353 AN: 1111932

Other (OTH) AF: 0.141 AC: 8517 AN: 60384

GnomAD4 genome AF: 0.118 AC: 17976 AN: 152132 Hom.: 1211 Cov.: 32 AF XY: 0.114 AC XY: 8514 AN XY: 74380

African (AFR) AF: 0.0779 AC: 3234 AN: 41504

American (AMR) AF: 0.129 AC: 1973 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5178

South Asian (SAS) AF: 0.0534 AC: 257 AN: 4814

European-Finnish (FIN) AF: 0.108 AC: 1139 AN: 10590

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10145 AN: 67972

Other (OTH) AF: 0.141 AC: 298 AN: 2108

Alfa AF: 0.124 Hom.: 514

Bravo AF: 0.121

TwinsUK AF: 0.141 AC: 522

ALSPAC AF: 0.124 AC: 478

ESP6500AA AF: 0.0797 AC: 351

ESP6500EA AF: 0.150 AC: 1287

ExAC AF: 0.118 AC: 14388

Asia WGS AF: 0.0350 AC: 121 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L;.
PhyloP100		0.50
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.075
Sift	Benign	0.096	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.012	B;.
Vest4		0.072
MPC		0.60
ClinPred		0.0074	T
GERP RS		3.2
Varity_R		0.059
gMVP		0.19
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: rs11578466; hg19: chr1-221057739; COSMIC: COSV65044591; COSMIC: COSV65044591;