12-54054291-C-T

Variant names:

• chr12-54054291-C-T
• rs138201582
• NM_153633.3:c.369C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_153633.3(HOXC4):​c.369C>T​(p.Asp123Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,607,834 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0040 (37 hom.)
• Consequence: HOXC4 NM_153633.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15
• Publications: 1 publications found

Genes affected

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]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 12-54054291-C-T is Benign according to our data. Variant chr12-54054291-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2643052.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS2: High AC in GnomAd4 at 563 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXC4	NM_153633.3	c.369C>T	p.Asp123Asp	synonymous_variant	Exon 1 of 2	ENST00000430889.3	NP_705897.1
HOXC4	NM_014620.6	c.369C>T	p.Asp123Asp	synonymous_variant	Exon 3 of 4		NP_055435.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXC4	ENST00000430889.3	c.369C>T	p.Asp123Asp	synonymous_variant	Exon 1 of 2	1	NM_153633.3	ENSP00000399808.2
HOXC4	ENST00000303406.4	c.369C>T	p.Asp123Asp	synonymous_variant	Exon 3 of 4	1		ENSP00000305973.4

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 563 AN: 151902 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00408

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00397 AC: 956 AN: 240752 AF XY: 0.00411

Gnomad AFR exome AF: 0.000590

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00221

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00399 AC: 5805 AN: 1455818 Hom.: 37 Cov.: 34 AF XY: 0.00408 AC XY: 2952 AN XY: 723862

African (AFR) AF: 0.000992 AC: 33 AN: 33250

American (AMR) AF: 0.00322 AC: 142 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 822 AN: 25906

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39612

South Asian (SAS) AF: 0.00269 AC: 231 AN: 85822

European-Finnish (FIN) AF: 0.00194 AC: 102 AN: 52486

Middle Eastern (MID) AF: 0.0165 AC: 94 AN: 5692

European-Non Finnish (NFE) AF: 0.00366 AC: 4057 AN: 1108844

Other (OTH) AF: 0.00538 AC: 323 AN: 60056

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152016 Hom.: 6 Cov.: 31 AF XY: 0.00355 AC XY: 264 AN XY: 74310

African (AFR) AF: 0.000530 AC: 22 AN: 41478

American (AMR) AF: 0.00621 AC: 95 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4810

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10562

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00408 AC: 277 AN: 67952

Other (OTH) AF: 0.00570 AC: 12 AN: 2106

Alfa AF: 0.00575 Hom.: 4

Bravo AF: 0.00333

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00600

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HOXC4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		1.2
PromoterAI		0.0034	Neutral
Mutation Taster		=94/6	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: rs138201582; hg19: chr12-54448075;