7-27130526-T-G

Position:

• chr7-27130526-T-G

Variant summary

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

The NM_002141.5(HOXA4):​c.208A>C​(p.Thr70Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.966 in 1,350,112 control chromosomes in the GnomAD database, including 629,619 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.95 (67702 hom., cov: 31)
  • Exomes 𝑓: 0.97 (561917 hom.)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.309

Genes affected

HOXA4 (HGNC:5105): (homeobox A4) 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. [provided by RefSeq, Jul 2008]

HOXA3 (HGNC:5104): (homeobox A3) 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. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000273433 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.4554937E-7).
• BP6: Variant 7-27130526-T-G is Benign according to our data. Variant chr7-27130526-T-G is described in ClinVar as [Benign]. Clinvar id is 1269767.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA4	NM_002141.5	c.208A>C	p.Thr70Pro	missense_variant	1/2	ENST00000360046.10	NP_002132.3
HOXA3	NM_153631.3	c.-389-3456A>C		intron_variant		ENST00000612286.5	NP_705895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA4	ENST00000360046.10	c.208A>C	p.Thr70Pro	missense_variant	1/2	1	NM_002141.5	ENSP00000353151.5
HOXA3	ENST00000612286.5	c.-389-3456A>C		intron_variant		2	NM_153631.3	ENSP00000484411.1

Frequencies

GnomAD3 genomes AF: 0.948 AC: 142497 AN: 150294 Hom.: 67652 Cov.: 31

Gnomad AFR AF: 0.895

Gnomad AMI AF: 0.968

Gnomad AMR AF: 0.966

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.944

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.970

Gnomad OTH AF: 0.944

GnomAD3 exomes AF: 0.962 AC: 42548 AN: 44206 Hom.: 20495 AF XY: 0.960 AC XY: 24186 AN XY: 25196

Gnomad AFR exome AF: 0.909

Gnomad AMR exome AF: 0.973

Gnomad ASJ exome AF: 0.979

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.936

Gnomad FIN exome AF: 0.959

Gnomad NFE exome AF: 0.972

Gnomad OTH exome AF: 0.962

GnomAD4 exome AF: 0.968 AC: 1161005 AN: 1199712 Hom.: 561917 Cov.: 50 AF XY: 0.967 AC XY: 564412 AN XY: 583632

Gnomad4 AFR exome AF: 0.895

Gnomad4 AMR exome AF: 0.971

Gnomad4 ASJ exome AF: 0.978

Gnomad4 EAS exome AF: 0.997

Gnomad4 SAS exome AF: 0.937

Gnomad4 FIN exome AF: 0.961

Gnomad4 NFE exome AF: 0.970

Gnomad4 OTH exome AF: 0.963

GnomAD4 genome AF: 0.948 AC: 142600 AN: 150400 Hom.: 67702 Cov.: 31 AF XY: 0.947 AC XY: 69514 AN XY: 73396

Gnomad4 AFR AF: 0.895

Gnomad4 AMR AF: 0.967

Gnomad4 ASJ AF: 0.982

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.944

Gnomad4 FIN AF: 0.958

Gnomad4 NFE AF: 0.970

Gnomad4 OTH AF: 0.945

Alfa AF: 0.957 Hom.: 7469

TwinsUK AF: 0.971 AC: 3601

ALSPAC AF: 0.973 AC: 3749

ESP6500AA AF: 0.937 AC: 1805

ESP6500EA AF: 0.977 AC: 4365

ExAC AF: 0.942 AC: 48213

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

HOXA4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.60
DEOGEN2	Benign	0.023	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.12	.;.;T
MetaRNN	Benign	5.5e-7	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.97	N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.95	.;N;N
REVEL	Benign	0.060
Sift	Benign	1.0	.;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.018
MPC		0.67
ClinPred		0.0018	T
GERP RS		2.2
Varity_R		0.12
gMVP		0.22

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: rs6944345; hg19: chr7-27170145; COSMIC: COSV57827978; COSMIC: COSV57827978;