12-54033388-A-G

Variant names:

• chr12-54033388-A-G
• rs146874223
• NM_018953.4:c.266A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018953.4(HOXC5):​c.266A>G​(p.Asp89Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,612,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: HOXC5 NM_018953.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78
• Publications: 0 publications found

Genes affected

HOXC5 (HGNC:5127): (homeobox C5) This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes and consist of 9 to 11 genes arranged in tandem. This gene, HOXC5, is one of several homeobox HOXC genes located in a cluster on chromosome 12. Three genes, HOXC5, HOXC4 and HOXC6, share a 5' non-coding exon. Transcripts may include the shared exon spliced to the gene-specific exons, or they may include only the gene-specific exons. Two alternatively spliced variants have been described for HOXC5. The transcript variant which includes the shared exon apparently doesn't encode a protein. The protein-coding transcript variant contains gene-specific exons only. [provided by RefSeq, Jul 2008]

HOXC4 (HGNC:5126): (homeobox C4) This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes and consist of 9 to 11 genes arranged in tandem. This gene, HOXC4, is one of several homeobox HOXC genes located in a cluster on chromosome 12. Three genes, HOXC5, HOXC4 and HOXC6, share a 5' non-coding exon. Transcripts may include the shared exon spliced to the gene-specific exons, or they may include only the gene-specific exons. Two alternatively spliced variants that encode the same protein have been described for HOXC4. Transcript variant one includes the shared exon, and transcript variant two includes only gene-specific exons. [provided by RefSeq, Jul 2008]

ENSG00000273049 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.114305794).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018953.4. 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
	HOXC5	NM_018953.4	MANE Select	c.266A>G	p.Asp89Gly	missense	Exon 1 of 2	NP_061826.1	Q00444
	HOXC4	NM_014620.6		c.-124+15974A>G		intron	N/A	NP_055435.2
	HOXC5	NR_003084.3		n.528-890A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXC5	ENST00000312492.3	TSL:1 MANE Select	c.266A>G	p.Asp89Gly	missense	Exon 1 of 2	ENSP00000309336.2	Q00444
	HOXC4	ENST00000303406.4	TSL:1	c.-124+15974A>G		intron	N/A	ENSP00000305973.4	P09017
	ENSG00000273049	ENST00000513209.1	TSL:3	c.167-890A>G		intron	N/A	ENSP00000476742.1	V9GYH0

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000221 AC: 54 AN: 244310 AF XY: 0.000248

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000420

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000292 AC: 427 AN: 1460494 Hom.: 0 Cov.: 31 AF XY: 0.000286 AC XY: 208 AN XY: 726562

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000672 AC: 3 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.0000568 AC: 3 AN: 52836

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5706

European-Non Finnish (NFE) AF: 0.000367 AC: 408 AN: 1111568

Other (OTH) AF: 0.000149 AC: 9 AN: 60324

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74322

African (AFR) AF: 0.0000483 AC: 2 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

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	Benign	0.060
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.010
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.23
Sift	Benign	0.19	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.28
MVP		0.90
MPC		0.33
ClinPred		0.024	T
GERP RS		4.8
PromoterAI		-0.031	Neutral
Varity_R		0.12
gMVP		0.38
Mutation Taster		=90/10	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

dbSNP: rs146874223; hg19: chr12-54427172;