7-27095695-C-T

Position:

• chr7-27095695-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005522.5(HOXA1):​c.218G>A​(p.Arg73His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.779 in 1,554,656 control chromosomes in the GnomAD database, including 459,498 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.74 (42759 hom., cov: 28)
  • Exomes 𝑓: 0.78 (416739 hom.)
• Consequence: HOXA1 NM_005522.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5935766E-7).
• BP6: Variant 7-27095695-C-T is Benign according to our data. Variant chr7-27095695-C-T is described in ClinVar as [Benign]. Clinvar id is 369585.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-27095695-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA1	NM_005522.5	c.218G>A	p.Arg73His	missense_variant	1/2	ENST00000643460.2	NP_005513.2
HOXA1	NM_153620.3	c.218G>A	p.Arg73His	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>A	p.Arg73His	missense_variant	1/2		NM_005522.5	ENSP00000494260	P1
HOXA1	ENST00000355633.5	c.218G>A	p.Arg73His	missense_variant	1/3	1		ENSP00000347851
HOTAIRM1	ENST00000495032.1	n.26+23C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.741 AC: 110959 AN: 149828 Hom.: 42740 Cov.: 28

Gnomad AFR AF: 0.475

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.829

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.843

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.765

GnomAD3 exomes AF: 0.757 AC: 173420 AN: 229120 Hom.: 64066 AF XY: 0.760 AC XY: 93712 AN XY: 123298

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.799

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.911

Gnomad SAS exome AF: 0.823

Gnomad FIN exome AF: 0.766

Gnomad NFE exome AF: 0.751

Gnomad OTH exome AF: 0.758

GnomAD4 exome AF: 0.783 AC: 1099656 AN: 1404714 Hom.: 416739 Cov.: 56 AF XY: 0.785 AC XY: 549262 AN XY: 699280

Gnomad4 AFR exome AF: 0.450

Gnomad4 AMR exome AF: 0.825

Gnomad4 ASJ exome AF: 0.787

Gnomad4 EAS exome AF: 0.933

Gnomad4 SAS exome AF: 0.863

Gnomad4 FIN exome AF: 0.789

Gnomad4 NFE exome AF: 0.779

Gnomad4 OTH exome AF: 0.778

GnomAD4 genome AF: 0.740 AC: 111018 AN: 149942 Hom.: 42759 Cov.: 28 AF XY: 0.746 AC XY: 54622 AN XY: 73194

Gnomad4 AFR AF: 0.475

Gnomad4 AMR AF: 0.830

Gnomad4 ASJ AF: 0.836

Gnomad4 EAS AF: 0.979

Gnomad4 SAS AF: 0.926

Gnomad4 FIN AF: 0.825

Gnomad4 NFE AF: 0.829

Gnomad4 OTH AF: 0.767

Alfa AF: 0.831 Hom.: 63320

Bravo AF: 0.720

TwinsUK AF: 0.852 AC: 3158

ALSPAC AF: 0.857 AC: 3304

ESP6500AA AF: 0.485 AC: 2136

ESP6500EA AF: 0.856 AC: 7364

ExAC AF: 0.764 AC: 92216

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bilateral microtia-deafness-cleft palate syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.94
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.18	.;T;T
MetaRNN	Benign	5.6e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.0	N;.;N
REVEL	Benign	0.026
Sift	Benign	0.89	T;.;T
Sift4G	Benign	0.36	T;.;T
Polyphen		0.0	.;.;B
Vest4		0.060
MPC		0.45
ClinPred		0.0049	T
GERP RS		2.5
gMVP		0.38

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; COSMIC: COSV56065044; COSMIC: COSV56065044;