chr7-27095719-T-G

Variant names:

• chr7-27095719-T-G
• rs146782650
• NM_005522.5:c.194A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_005522.5(HOXA1):​c.194A>C​(p.His65Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,604,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: HOXA1 NM_005522.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.51
• Publications: 0 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012768209).
• BP6: Variant 7-27095719-T-G is Benign according to our data. Variant chr7-27095719-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 359969.

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.194A>C	p.His65Pro	missense	Exon 1 of 2	NP_005513.2	P49639-1
	HOXA1	NM_153620.3		c.194A>C	p.His65Pro	missense	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.194A>C	p.His65Pro	missense	Exon 1 of 2	ENSP00000494260.2	P49639-1
	HOXA1	ENST00000355633.5	TSL:1	c.194A>C	p.His65Pro	missense	Exon 1 of 3	ENSP00000347851.5	E7ERT8
	HOTAIRM1	ENST00000495032.1	TSL:5	n.26+47T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000365 AC: 55 AN: 150718 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.0000959

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000652

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000439 AC: 108 AN: 245984 AF XY: 0.000413

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00194

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000637

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000524 AC: 762 AN: 1453656 Hom.: 0 Cov.: 38 AF XY: 0.000524 AC XY: 379 AN XY: 723106

African (AFR) AF: 0.0000598 AC: 2 AN: 33430

American (AMR) AF: 0.000180 AC: 8 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00213 AC: 55 AN: 25862

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39632

South Asian (SAS) AF: 0.000221 AC: 19 AN: 85880

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.000589 AC: 651 AN: 1105832

Other (OTH) AF: 0.000399 AC: 24 AN: 60094

GnomAD4 genome AF: 0.000365 AC: 55 AN: 150832 Hom.: 0 Cov.: 30 AF XY: 0.000272 AC XY: 20 AN XY: 73634

African (AFR) AF: 0.0000727 AC: 3 AN: 41248

American (AMR) AF: 0.0000661 AC: 1 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4724

European-Finnish (FIN) AF: 0.0000959 AC: 1 AN: 10430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000652 AC: 44 AN: 67518

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000387 AC: 47

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.71
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.27	T
PhyloP100		1.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.2	N
REVEL	Uncertain	0.32
Sift	Benign	0.42	T
Sift4G	Benign	0.33	T
Polyphen		0.95	P
Vest4		0.24
MVP		0.97
MPC		1.2
ClinPred		0.015	T
GERP RS		4.1
PromoterAI		0.0018	Neutral
gMVP		0.47
Mutation Taster		=74/26	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: rs146782650; hg19: chr7-27135338; COSMIC: COSV56065521; COSMIC: COSV56065521;