NM_005522.5:c.207C>T

Variant names:

• chr7-27095706-G-A
• rs577426612
• NM_005522.5:c.207C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005522.5(HOXA1):​c.207C>T​(p.His69His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000605 in 1,605,770 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00059 (6 hom.)
• Consequence: HOXA1 NM_005522.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.810
• Publications: 2 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 7-27095706-G-A is Benign according to our data. Variant chr7-27095706-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 359967.
• BP7: Synonymous conserved (PhyloP=0.81 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.207C>T	p.His69His	synonymous	Exon 1 of 2	NP_005513.2	P49639-1
	HOXA1	NM_153620.3		c.207C>T	p.His69His	synonymous	Exon 1 of 3	NP_705873.3	P49639-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA1	ENST00000643460.2	MANE Select	c.207C>T	p.His69His	synonymous	Exon 1 of 2	ENSP00000494260.2	P49639-1
	HOXA1	ENST00000355633.5	TSL:1	c.207C>T	p.His69His	synonymous	Exon 1 of 3	ENSP00000347851.5	E7ERT8
	HOTAIRM1	ENST00000495032.1	TSL:5	n.26+34G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000706 AC: 107 AN: 151492 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.000852

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.000965

GnomAD2 exomes AF: 0.00146 AC: 364 AN: 248572 AF XY: 0.00145

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0148

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000594 AC: 864 AN: 1454158 Hom.: 6 Cov.: 38 AF XY: 0.000585 AC XY: 423 AN XY: 722882

African (AFR) AF: 0.000269 AC: 9 AN: 33404

American (AMR) AF: 0.000315 AC: 14 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25476

East Asian (EAS) AF: 0.0137 AC: 544 AN: 39650

South Asian (SAS) AF: 0.00158 AC: 132 AN: 83542

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53222

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5628

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1108814

Other (OTH) AF: 0.000784 AC: 47 AN: 59920

GnomAD4 genome AF: 0.000706 AC: 107 AN: 151612 Hom.: 0 Cov.: 31 AF XY: 0.000891 AC XY: 66 AN XY: 74052

African (AFR) AF: 0.000145 AC: 6 AN: 41464

American (AMR) AF: 0.000263 AC: 4 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3356

East Asian (EAS) AF: 0.0167 AC: 86 AN: 5146

South Asian (SAS) AF: 0.000853 AC: 4 AN: 4692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67864

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000303 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Bosley-Salih-Alorainy syndrome (1)
-	-	1	HOXA1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.3
DANN	Benign	0.94
PhyloP100		0.81
PromoterAI		0.024	Neutral
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: rs577426612; hg19: chr7-27135325;