7-27143364-C-G

Variant names:

• chr7-27143364-C-G
• rs776598451
• NM_019102.4:c.244G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_019102.4(HOXA5):​c.244G>C​(p.Ala82Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000259 in 1,431,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: HOXA5 NM_019102.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30
• Publications: 1 publications found

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]

ENSG00000273433 (HGNC:):

HOXA-AS3 (HGNC:43748): (HOXA cluster antisense RNA 3)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4227314).
• BS2: High AC in GnomAdExome4 at 37 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019102.4. 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
	HOXA5	NM_019102.4	MANE Select	c.244G>C	p.Ala82Pro	missense	Exon 1 of 2	NP_061975.2
	HOXA3	NM_153631.3	MANE Select	c.-493-3178G>C		intron	N/A	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.-609-3178G>C		intron	N/A	NP_001371264.1	O43365

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA5	ENST00000222726.4	TSL:1 MANE Select	c.244G>C	p.Ala82Pro	missense	Exon 1 of 2	ENSP00000222726.3	P20719
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.-493-3178G>C		intron	N/A	ENSP00000484411.1	O43365
	HOXA3	ENST00000851228.1		c.-308-3178G>C		intron	N/A	ENSP00000521287.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000103 AC: 2 AN: 194704 AF XY: 0.00000922

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: 0.0000236

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000259 AC: 37 AN: 1431152 Hom.: 0 Cov.: 31 AF XY: 0.0000225 AC XY: 16 AN XY: 710808

African (AFR) AF: 0.00 AC: 0 AN: 32650

American (AMR) AF: 0.00 AC: 0 AN: 40642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25246

East Asian (EAS) AF: 0.00 AC: 0 AN: 38600

South Asian (SAS) AF: 0.00 AC: 0 AN: 84084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.0000336 AC: 37 AN: 1100850

Other (OTH) AF: 0.00 AC: 0 AN: 59232

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000871 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.056
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.035	N
PhyloP100		2.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.33
Sift	Benign	0.23	T
Sift4G	Benign	0.26	T
Polyphen		0.34	B
Vest4		0.39
MutPred		0.32		Gain of glycosylation at A82 (P = 0.0093)
MVP		0.80
MPC		0.94
ClinPred		0.27	T
GERP RS		4.5
PromoterAI		-0.055	Neutral
Varity_R		0.18
gMVP		0.26
Mutation Taster		=57/43	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: rs776598451; hg19: chr7-27182983;