1-220880308-G-T

Variant names:

• chr1-220880308-G-T
• rs12041280
• NM_021958.4:c.451G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021958.4(HLX):​c.451G>T​(p.Ala151Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HLX NM_021958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052794635).

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.451G>T	p.Ala151Ser	missense	Exon 1 of 4	NP_068777.1	Q14774
	HLX-AS1	NR_046901.1		n.-168C>A		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.451G>T	p.Ala151Ser	missense	Exon 1 of 4	ENSP00000355870.5	Q14774
	ENSG00000286231	ENST00000651706.1		n.843-886G>T		intron	N/A	ENSP00000499157.1	A0A494C1P3
	HLX	ENST00000944514.1		c.451G>T	p.Ala151Ser	missense	Exon 1 of 4	ENSP00000614573.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461370 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726956

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111664

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.8
DANN	Benign	0.92
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.10
Sift	Benign	0.19	T
Sift4G	Benign	0.89	T
Polyphen		0.018	B
Vest4		0.20
MutPred		0.12		Gain of glycosylation at A151 (P = 0.02)
MVP		0.27
MPC		0.41
ClinPred		0.11	T
GERP RS		-0.52
Varity_R		0.043
gMVP		0.20
Mutation Taster		=99/1	polymorphism

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: rs12041280; hg19: chr1-221053650;