chr1-220879953-C-G

Position:

• chr1-220879953-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLX	NM_021958.4	c.96C>G	p.Phe32Leu	missense_variant	1/4	ENST00000366903.8	NP_068777.1
HLX-AS1	NR_046901.1	n.188G>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLX	ENST00000366903.8	c.96C>G	p.Phe32Leu	missense_variant	1/4	1	NM_021958.4	ENSP00000355870.5
ENSG00000286231	ENST00000651706.1	n.843-1241C>G		intron_variant				ENSP00000499157.1
HLX	ENST00000549319.2	n.523C>G		non_coding_transcript_exon_variant	1/1	6
HLX-AS1	ENST00000552026.1	n.188G>C		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2024

The c.96C>G (p.F32L) alteration is located in exon 1 (coding exon 1) of the HLX gene. This alteration results from a C to G substitution at nucleotide position 96, causing the phenylalanine (F) at amino acid position 32 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-221053295;