chr7-27141861-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_019102.4(HOXA5):​c.787G>A​(p.Ala263Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,461,820 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A263V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: HOXA5 NM_019102.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15721345).
• BS2: High AC in GnomAdExome4 at 48 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.787G>A	p.Ala263Thr	missense	Exon 2 of 2	NP_061975.2
	HOXA3	NM_153631.3	MANE Select	c.-493-1675G>A		intron	N/A	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.-609-1675G>A		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>A	p.Ala263Thr	missense	Exon 2 of 2	ENSP00000222726.3	P20719
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.-493-1675G>A		intron	N/A	ENSP00000484411.1	O43365
	HOXA3	ENST00000851228.1		c.-308-1675G>A		intron	N/A	ENSP00000521287.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251484 AF XY: 0.000118

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: 0.0000328 AC: 48 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000556 AC: 48 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000741 AC: 9

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	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T
Sift4G	Benign	0.63	T
Polyphen		0.99	D
Vest4		0.38
MutPred		0.15		Loss of MoRF binding (P = 0.1121)
MVP		0.78
MPC		0.72
ClinPred		0.16	T
GERP RS		5.1
Varity_R		0.16
gMVP		0.86
Mutation Taster		=75/25	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;