7-27141866-A-G

Variant names:

• chr7-27141866-A-G
• rs557164565
• NM_019102.4:c.782T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_019102.4(HOXA5):​c.782T>C​(p.Met261Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: HOXA5 NM_019102.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.84

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXA5	NM_019102.4	c.782T>C	p.Met261Thr	missense_variant	Exon 2 of 2	ENST00000222726.4	NP_061975.2
HOXA3	NM_153631.3	c.-493-1680T>C		intron_variant	Intron 1 of 5	ENST00000612286.5	NP_705895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXA5	ENST00000222726.4	c.782T>C	p.Met261Thr	missense_variant	Exon 2 of 2	1	NM_019102.4	ENSP00000222726.3
HOXA3	ENST00000612286.5	c.-493-1680T>C		intron_variant	Intron 1 of 5	2	NM_153631.3	ENSP00000484411.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251488 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135918

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 SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727240

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: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.782T>C (p.M261T) alteration is located in exon 2 (coding exon 2) of the HOXA5 gene. This alteration results from a T to C substitution at nucleotide position 782, causing the methionine (M) at amino acid position 261 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	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.17	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.64
Sift	Benign	0.10	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.96	D
Vest4		0.62
MutPred		0.29		Gain of glycosylation at M261 (P = 0.0453);
MVP		0.89
MPC		0.88
ClinPred		0.24	T
GERP RS		5.1
Varity_R		0.45
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs557164565; hg19: chr7-27181485;