12-54033155-G-C

Variant names:

• chr12-54033155-G-C
• rs35606176
• NM_018953.4:c.33G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018953.4(HOXC5):​c.33G>C​(p.Lys11Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,672 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (16 hom.)
• Consequence: HOXC5 NM_018953.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.97
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008505672).
• BP6: Variant 12-54033155-G-C is Benign according to our data. Variant chr12-54033155-G-C is described in ClinVar as [Benign]. Clinvar id is 783664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00894 (1362/152284) while in subpopulation AFR AF = 0.0314 (1305/41542). AF 95% confidence interval is 0.03. There are 17 homozygotes in GnomAd4. There are 643 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXC5	NM_018953.4	c.33G>C	p.Lys11Asn	missense_variant	Exon 1 of 2	ENST00000312492.3	NP_061826.1
HOXC4	NM_014620.6	c.-124+15741G>C		intron_variant	Intron 1 of 3		NP_055435.2
HOXC5	NR_003084.3	n.528-1123G>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXC5	ENST00000312492.3	c.33G>C	p.Lys11Asn	missense_variant	Exon 1 of 2	1	NM_018953.4	ENSP00000309336.2
HOXC4	ENST00000303406.4	c.-124+15741G>C		intron_variant	Intron 1 of 3	1		ENSP00000305973.4
ENSG00000273049	ENST00000513209.1	c.167-1123G>C		intron_variant	Intron 1 of 1	3		ENSP00000476742.1
ENSG00000273046	ENST00000512206.1	n.306-1123G>C		intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes AF: 0.00894 AC: 1360 AN: 152166 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00235 AC: 591 AN: 251254 AF XY: 0.00163

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000903 AC: 1319 AN: 1461388 Hom.: 16 Cov.: 31 AF XY: 0.000746 AC XY: 542 AN XY: 726880

African (AFR) AF: 0.0333 AC: 1113 AN: 33470

American (AMR) AF: 0.000827 AC: 37 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53408

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111598

Other (OTH) AF: 0.00179 AC: 108 AN: 60374

GnomAD4 genome AF: 0.00894 AC: 1362 AN: 152284 Hom.: 17 Cov.: 32 AF XY: 0.00864 AC XY: 643 AN XY: 74452

African (AFR) AF: 0.0314 AC: 1305 AN: 41542

American (AMR) AF: 0.00255 AC: 39 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.000560 Hom.: 0

Bravo AF: 0.0102

ESP6500AA AF: 0.0331 AC: 146

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00320 AC: 388

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0085	T
MetaSVM	Uncertain	0.040	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.063	T
Polyphen		0.90	P
Vest4		0.43
MutPred		0.42		Loss of methylation at K11 (P = 0.0083);
MVP		0.92
MPC		0.91
ClinPred		0.020	T
GERP RS		5.3
PromoterAI		-0.018	Neutral
Varity_R		0.28
gMVP		0.47
Mutation Taster		=38/62	disease causing

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: rs35606176; hg19: chr12-54426939; COSMIC: COSV99060204; COSMIC: COSV99060204;