7-27143388-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_019102.4(HOXA5):​c.220G>A​(p.Ala74Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HOXA5
NM_019102.4 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44
Variant links:
Genes affected
HOXA5 (HGNC:5106): (homeobox A5) 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. Methylation of this gene may result in the loss of its expression and, since the encoded protein upregulates the tumor suppressor p53, this protein may play an important role in tumorigenesis. [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-AS3 (HGNC:43748): (HOXA cluster antisense RNA 3)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.30819678).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HOXA5NM_019102.4 linkc.220G>A p.Ala74Thr missense_variant Exon 1 of 2 ENST00000222726.4 NP_061975.2 P20719
HOXA3NM_153631.3 linkc.-493-3202G>A intron_variant Intron 1 of 5 ENST00000612286.5 NP_705895.1 O43365A4D182A0A024RA33B3KPN8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HOXA5ENST00000222726.4 linkc.220G>A p.Ala74Thr missense_variant Exon 1 of 2 1 NM_019102.4 ENSP00000222726.3 P20719
HOXA3ENST00000612286.5 linkc.-493-3202G>A intron_variant Intron 1 of 5 2 NM_153631.3 ENSP00000484411.1 O43365

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1449620
Hom.:
0
Cov.:
31
AF XY:
0.00000139
AC XY:
1
AN XY:
721010
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.220G>A (p.A74T) alteration is located in exon 1 (coding exon 1) of the HOXA5 gene. This alteration results from a G to A substitution at nucleotide position 220, causing the alanine (A) at amino acid position 74 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.0032
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Benign
0.21
T
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.069
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.70
T
M_CAP
Pathogenic
0.88
D
MetaRNN
Benign
0.31
T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
-0.14
N
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.25
N
REVEL
Benign
0.22
Sift
Benign
0.45
T
Sift4G
Benign
0.65
T
Polyphen
0.10
B
Vest4
0.31
MutPred
0.33
Gain of phosphorylation at A74 (P = 0.0067);
MVP
0.53
MPC
0.70
ClinPred
0.60
D
GERP RS
4.6
Varity_R
0.23
gMVP
0.27

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-27183007; API