NM_021958.4:c.96C>G

Variant names:

• chr1-220879953-C-G
• NM_021958.4:c.96C>G

Variant summary

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

The NM_021958.4(HLX):​c.96C>G​(p.Phe32Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HLX NM_021958.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.507
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.96C>G	p.Phe32Leu	missense	Exon 1 of 4	NP_068777.1	Q14774
	HLX-AS1	NR_046901.1		n.188G>C		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLX	ENST00000366903.8	TSL:1 MANE Select	c.96C>G	p.Phe32Leu	missense	Exon 1 of 4	ENSP00000355870.5	Q14774
	ENSG00000286231	ENST00000651706.1		n.843-1241C>G		intron	N/A	ENSP00000499157.1	A0A494C1P3
	HLX	ENST00000944514.1		c.96C>G	p.Phe32Leu	missense	Exon 1 of 4	ENSP00000614573.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.9	L
PhyloP100		0.51
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		0.92	P
Vest4		0.43
MutPred		0.45		Gain of disorder (P = 0.1154)
MVP		0.69
MPC		0.91
ClinPred		0.94	D
GERP RS		1.4
Varity_R		0.38
gMVP		0.72
Mutation Taster		=82/18	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

hg19: chr1-221053295;