chr1-220884507-G-T

Variant names:

• chr1-220884507-G-T
• rs748250119
• NM_021958.4:c.1270G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021958.4(HLX):​c.1270G>T​(p.Gly424Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G424S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HLX NM_021958.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.111
• 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:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09747115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLX	NM_021958.4	c.1270G>T	p.Gly424Cys	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.1270G>T	p.Gly424Cys	missense_variant	Exon 4 of 4	1	NM_021958.4	ENSP00000355870.5
HLX	ENST00000549319.2	n.5077G>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000286231	ENST00000651706.1	n.*578G>T		downstream_gene_variant				ENSP00000499157.1
HLX	ENST00000427693.1	c.*14G>T		downstream_gene_variant		3		ENSP00000408248.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.11
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.15
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.036	D
Polyphen		0.0080	B
Vest4		0.14
MutPred		0.30		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.67
MPC		0.77
ClinPred		0.10	T
GERP RS		1.0
Varity_R		0.14
gMVP		0.30
Mutation Taster		=92/8	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: rs748250119; hg19: chr1-221057849;