chr7-27095695-C-A

Variant names:

• chr7-27095695-C-A
• rs10951154
• NM_005522.5:c.218G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005522.5(HOXA1):​c.218G>T​(p.Arg73Leu) 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. 14/20 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: not found (cov: 28)
• Consequence: HOXA1 NM_005522.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• Publications: 67 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062097788).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005522.5. 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
	HOXA1	NM_005522.5	MANE Select	c.218G>T	p.Arg73Leu	missense	Exon 1 of 2	NP_005513.2
	HOXA1	NM_153620.3		c.218G>T	p.Arg73Leu	missense	Exon 1 of 3	NP_705873.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA1	ENST00000643460.2	MANE Select	c.218G>T	p.Arg73Leu	missense	Exon 1 of 2	ENSP00000494260.2
	HOXA1	ENST00000355633.5	TSL:1	c.218G>T	p.Arg73Leu	missense	Exon 1 of 3	ENSP00000347851.5
	HOTAIRM1	ENST00000495032.1	TSL:5	n.26+23C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 89710

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.95
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.060
Sift	Benign	0.65	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.26		Loss of solvent accessibility (P = 0.0052)
MVP		0.20
MPC		0.45
ClinPred		0.086	T
GERP RS		2.5
PromoterAI		0.016	Neutral
gMVP		0.46
Mutation Taster		=100/0	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: rs10951154; hg19: chr7-27135314;