NM_020834.3:c.1430G>A

Variant names:

• chr14-23275798-C-T
• rs532518305
• NM_020834.3:c.1430G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_020834.3(HOMEZ):​c.1430G>A​(p.Arg477Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,610,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R477W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: HOMEZ NM_020834.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.202

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04792148).
• BP6: Variant 14-23275798-C-T is Benign according to our data. Variant chr14-23275798-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3526164.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOMEZ	NM_020834.3	c.1430G>A	p.Arg477Gln	missense_variant	Exon 2 of 2	ENST00000357460.7	NP_065885.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOMEZ	ENST00000357460.7	c.1430G>A	p.Arg477Gln	missense_variant	Exon 2 of 2	1	NM_020834.3	ENSP00000350049.4
HOMEZ	ENST00000561013.3	c.1436G>A	p.Arg479Gln	missense_variant	Exon 3 of 3	2		ENSP00000453979.1
HOMEZ	ENST00000673724.1	c.1097G>A	p.Arg366Gln	missense_variant	Exon 3 of 3			ENSP00000501153.1
HOMEZ	ENST00000606731.2	c.920G>A	p.Arg307Gln	missense_variant	Exon 2 of 2	2		ENSP00000475307.3

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000649 AC: 16 AN: 246572 Hom.: 0 AF XY: 0.0000673 AC XY: 9 AN XY: 133654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000295 AC: 43 AN: 1458846 Hom.: 0 Cov.: 36 AF XY: 0.0000303 AC XY: 22 AN XY: 725382

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000744 AC: 9

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 25, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.8
DANN	Benign	0.83
DEOGEN2	Benign	0.0011	T;.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.14	N;.;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.22	N;N;.
REVEL	Benign	0.16
Sift	Benign	0.57	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.11	B;.;.
Vest4		0.078
MVP		0.84
MPC		0.29
ClinPred		0.029	T
GERP RS		1.8
Varity_R		0.065
gMVP		0.15

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

Other links and lift over

dbSNP: rs532518305; hg19: chr14-23745007; COSMIC: COSV100664158; COSMIC: COSV100664158;