Variant 14-23275967-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020834.3(HOMEZ):c.1261G>C(p.Asp421His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HOMEZ
NM_020834.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

Variant links:

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]

HOMEZ links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38836038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOMEZ	NM_020834.3 linkuse as main transcript	c.1261G>C	p.Asp421His	missense_variant	2/2	ENST00000357460.7	NP_065885.2	Q8IX15-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HOMEZ	ENST00000357460.7 linkuse as main transcript	c.1261G>C	p.Asp421His	missense_variant	2/2	1	NM_020834.3	ENSP00000350049.4	Q8IX15-1
HOMEZ	ENST00000561013.3 linkuse as main transcript	c.1267G>C	p.Asp423His	missense_variant	3/3	2		ENSP00000453979.1	Q8IX15-3
HOMEZ	ENST00000673724.1 linkuse as main transcript	c.928G>C	p.Asp310His	missense_variant	3/3			ENSP00000501153.1	A0A669KB72
HOMEZ	ENST00000606731.2 linkuse as main transcript	c.751G>C	p.Asp251His	missense_variant	2/2	2		ENSP00000475307.3	U3KPW8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

246154

Hom.:

AF XY:

0.00000749

AC XY:

AN XY:

133496

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000224

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460574

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.1261G>C (p.D421H) alteration is located in exon 2 (coding exon 2) of the HOMEZ gene. This alteration results from a G to C substitution at nucleotide position 1261, causing the aspartic acid (D) at amino acid position 421 to be replaced by a histidine (H). 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

0.78

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.053

T;.;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.8

D;D;.

REVEL

Benign

0.25

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.45

MutPred

0.47

Loss of catalytic residue at D421 (P = 0.0022);.;.;

MVP

0.38

MPC

0.96

ClinPred

0.76

GERP RS

5.8

Varity_R

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over