14-23275741-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020834.3(HOMEZ):c.1487T>C(p.Leu496Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOMEZ NM_020834.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

Genes affected

HOMEZ (HGNC:20164): (homeobox and leucine zipper encoding) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in cytosol; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOMEZ	NM_020834.3	c.1487T>C	p.Leu496Pro	missense_variant	2/2	ENST00000357460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOMEZ	ENST00000357460.7	c.1487T>C	p.Leu496Pro	missense_variant	2/2	1	NM_020834.3	P2
HOMEZ	ENST00000561013.3	c.1493T>C	p.Leu498Pro	missense_variant	3/3	2		A2
HOMEZ	ENST00000673724.1	c.1154T>C	p.Leu385Pro	missense_variant	3/3			A2
HOMEZ	ENST00000606731.2			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

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

May 25, 2022

The c.1487T>C (p.L496P) alteration is located in exon 2 (coding exon 2) of the HOMEZ gene. This alteration results from a T to C substitution at nucleotide position 1487, causing the leucine (L) at amino acid position 496 to be replaced by a proline (P). 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	0.81
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0070	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.93	N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.090	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.98	D;.
Vest4		0.72
MutPred		0.41		Loss of catalytic residue at L496 (P = 0.0064);.;
MVP		0.97
MPC		1.1
ClinPred		0.60	D
GERP RS		2.4
Varity_R		0.88
gMVP		0.69

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: chr14-23744950;