7-27095695-C-G

Position:

• chr7-27095695-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005522.5(HOXA1):​c.218G>C​(p.Arg73Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. R73H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 28)
  • Failed GnomAD Quality Control
• Consequence: HOXA1 NM_005522.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35

Genes affected

HOXA1 (HGNC:5099): (homeobox A1) 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. Two transcript variants encoding two different isoforms have been found for this gene, with only one of the isoforms containing the homeodomain region. [provided by RefSeq, Jul 2008]

HOTAIRM1 (HGNC:37117): (HOXA transcript antisense RNA, myeloid-specific 1) This non-coding locus is located in the HOX gene cluster. Transcription of this locus is induced by retinoic acid, and transcripts likely function in regulation of myelopoiesis through transcriptional activation of several genes in the HOXA cluster, in addition to several beta-2 integrins. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072838515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA1	NM_005522.5	c.218G>C	p.Arg73Pro	missense_variant	1/2	ENST00000643460.2	NP_005513.2
HOXA1	NM_153620.3	c.218G>C	p.Arg73Pro	missense_variant	1/3		NP_705873.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA1	ENST00000643460.2	c.218G>C	p.Arg73Pro	missense_variant	1/2		NM_005522.5	ENSP00000494260.2
HOXA1	ENST00000355633.5	c.218G>C	p.Arg73Pro	missense_variant	1/3	1		ENSP00000347851.5
HOTAIRM1	ENST00000495032.1	n.26+23C>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149918 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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.: 56

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 149918 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 73118

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.95
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.18	.;T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	2.1	N;.;N
REVEL	Benign	0.12
Sift	Benign	0.35	T;.;T
Sift4G	Benign	0.35	T;.;T
Polyphen		0.0	.;.;B
Vest4		0.11
MutPred		0.22		Gain of glycosylation at R73 (P = 0.0142);Gain of glycosylation at R73 (P = 0.0142);Gain of glycosylation at R73 (P = 0.0142);
MVP		0.24
MPC		0.53
ClinPred		0.11	T
GERP RS		2.5
gMVP		0.52

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: rs10951154; hg19: chr7-27135314;