7-27129538-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002141.5(HOXA4):​c.650G>C​(p.Arg217Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R217H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

HOXA4
NM_002141.5 missense

Scores

15
2
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.88
Variant links:
Genes affected
HOXA4 (HGNC:5105): (homeobox A4) 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. [provided by RefSeq, Jul 2008]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HOXA4NM_002141.5 linkc.650G>C p.Arg217Pro missense_variant Exon 2 of 2 ENST00000360046.10 NP_002132.3 Q00056
HOXA3NM_153631.3 linkc.-389-2468G>C intron_variant Intron 2 of 5 ENST00000612286.5 NP_705895.1 O43365A4D182A0A024RA33B3KPN8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HOXA4ENST00000360046.10 linkc.650G>C p.Arg217Pro missense_variant Exon 2 of 2 1 NM_002141.5 ENSP00000353151.5 Q00056
HOXA3ENST00000612286.5 linkc.-389-2468G>C intron_variant Intron 2 of 5 2 NM_153631.3 ENSP00000484411.1 O43365

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
33
DANN
Benign
0.92
DEOGEN2
Pathogenic
0.89
D;D;D
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
.;.;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.91
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H;H
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-6.9
.;D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.89
MutPred
0.64
Gain of ubiquitination at K216 (P = 0.0155);Gain of ubiquitination at K216 (P = 0.0155);Gain of ubiquitination at K216 (P = 0.0155);
MVP
0.99
MPC
1.7
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.96
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145032542; hg19: chr7-27169157; API