7-27108079-G-C

Variant names:

• chr7-27108079-G-C
• rs746997972
• NM_153631.3:c.1168C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153631.3(HOXA3):​c.1168C>G​(p.His390Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H390N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HOXA3 NM_153631.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.76
• Publications: 0 publications found

Genes affected

HOXA3 (HGNC:5104): (homeobox A3) In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HOXA-AS2 (HGNC:43745): (HOXA cluster antisense RNA 2) This gene produces a long non-coding RNA that promotes cell proliferation. This transcript may interact with enhancer of zeste homolog 2 Polycomb repressive complex to repress gene expression. [provided by RefSeq, Dec 2017]

ENSG00000293629 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153631.3. 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
	HOXA3	NM_153631.3	MANE Select	c.1168C>G	p.His390Asp	missense	Exon 6 of 6	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.1168C>G	p.His390Asp	missense	Exon 7 of 7	NP_001371264.1	O43365
	HOXA3	NM_001384336.1		c.1168C>G	p.His390Asp	missense	Exon 5 of 5	NP_001371265.1	O43365

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.1168C>G	p.His390Asp	missense	Exon 6 of 6	ENSP00000484411.1	O43365
	HOXA3	ENST00000396352.8	TSL:1	c.1168C>G	p.His390Asp	missense	Exon 3 of 3	ENSP00000379640.3	O43365
	HOXA3	ENST00000317201.7	TSL:5	c.1168C>G	p.His390Asp	missense	Exon 5 of 5	ENSP00000324884.2	O43365

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248450 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000137 AC: 2 AN: 1460602 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726494

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111178

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.77
Sift	Benign	0.051	T
Sift4G	Benign	0.062	T
Polyphen		1.0	D
Vest4		0.72
MutPred		0.34		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.86
MPC		0.79
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.63
Mutation Taster		=25/75	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: rs746997972; hg19: chr7-27147698;