7-27141861-C-G

Variant names:

• chr7-27141861-C-G
• rs766494765
• NM_019102.4:c.787G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_019102.4(HOXA5):​c.787G>C​(p.Ala263Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. A263T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: HOXA5 NM_019102.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.63
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3786822).

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.787G>C	p.Ala263Pro	missense	Exon 2 of 2	NP_061975.2
	HOXA3	NM_153631.3	MANE Select	c.-493-1675G>C		intron	N/A	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.-609-1675G>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.787G>C	p.Ala263Pro	missense	Exon 2 of 2	ENSP00000222726.3	P20719
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.-493-1675G>C		intron	N/A	ENSP00000484411.1	O43365
	HOXA3	ENST00000851228.1		c.-308-1675G>C		intron	N/A	ENSP00000521287.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.55	N
PhyloP100		4.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.41
Sift	Benign	0.24	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.21		Loss of MoRF binding (P = 0.0382)
MVP		0.74
MPC		1.9
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.72
gMVP		0.93
Mutation Taster		=59/41	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: rs766494765; hg19: chr7-27181480;