chr7-27130175-G-C

Position:

• chr7-27130175-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002141.5(HOXA4):​c.559C>G​(p.Leu187Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,593,846 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (7 hom.)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.06

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005851716).
• BP6: Variant 7-27130175-G-C is Benign according to our data. Variant chr7-27130175-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3052573.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA4	NM_002141.5	c.559C>G	p.Leu187Val	missense_variant	1/2	ENST00000360046.10	NP_002132.3
HOXA3	NM_153631.3	c.-389-3105C>G		intron_variant		ENST00000612286.5	NP_705895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXA4	ENST00000360046.10	c.559C>G	p.Leu187Val	missense_variant	1/2	1	NM_002141.5	ENSP00000353151.5
HOXA3	ENST00000612286.5	c.-389-3105C>G		intron_variant		2	NM_153631.3	ENSP00000484411.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152056 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00128 AC: 272 AN: 212480 Hom.: 0 AF XY: 0.00141 AC XY: 167 AN XY: 118638

Gnomad AFR exome AF: 0.000512

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00293

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00375

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.00142 AC: 2040 AN: 1441672 Hom.: 7 Cov.: 30 AF XY: 0.00153 AC XY: 1096 AN XY: 717310

Gnomad4 AFR exome AF: 0.000307

Gnomad4 AMR exome AF: 0.000571

Gnomad4 ASJ exome AF: 0.00388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00398

Gnomad4 FIN exome AF: 0.0000680

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152174 Hom.: 0 Cov.: 34 AF XY: 0.00109 AC XY: 81 AN XY: 74396

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00372

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00125

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00111 AC: 9

ExAC AF: 0.00125 AC: 149

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HOXA4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 24, 2021

This variant is classified as likely 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	0.080
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.029	T;T;T
Eigen	Benign	0.019
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	.;.;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.88	L;L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.020	.;N;N
REVEL	Benign	0.25
Sift	Benign	0.60	.;T;T
Sift4G	Benign	0.85	T;T;T
Polyphen		0.033	B;B;B
Vest4		0.083
MVP		0.92
MPC		0.65
ClinPred		0.011	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.39

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: rs200014123; hg19: chr7-27169794;