7-27101301-G-A

Variant names:

• chr7-27101301-G-A
• rs119489104
• NM_006735.4:c.556C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_006735.4(HOXA2):​c.556C>T​(p.Gln186*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HOXA2 NM_006735.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.97
• Publications: 8 publications found

Genes affected

HOXA2 (HGNC:5103): (homeobox A2) 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. The encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development. [provided by RefSeq, Jul 2008]

HOXA2 Gene-Disease associations (from GenCC):

• bilateral microtia-deafness-cleft palate syndrome

  Inheritance: AD, AR, SD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• microtia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000293629 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006735.4. 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
	HOXA2	NM_006735.4	MANE Select	c.556C>T	p.Gln186*	stop_gained	Exon 2 of 2	NP_006726.1	O43364

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA2	ENST00000222718.7	TSL:1 MANE Select	c.556C>T	p.Gln186*	stop_gained	Exon 2 of 2	ENSP00000222718.5	O43364
	HOXA2	ENST00000612779.1	TSL:6	n.1386C>T		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000293629	ENST00000716605.1		n.310+4913G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		10
Vest4		0.95
GERP RS		5.5
Mutation Taster		=52/148	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs119489104; hg19: chr7-27140920;