7-27130491-C-G

Position:

• chr7-27130491-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_002141.5(HOXA4):​c.243G>C​(p.Glu81Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,279,822 control chromosomes in the GnomAD database, including 1 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.24

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0051670074).
• BP6: Variant 7-27130491-C-G is Benign according to our data. Variant chr7-27130491-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3034411.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA4	NM_002141.5	c.243G>C	p.Glu81Asp	missense_variant	1/2	ENST00000360046.10	NP_002132.3
HOXA3	NM_153631.3	c.-389-3421G>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.243G>C	p.Glu81Asp	missense_variant	1/2	1	NM_002141.5	ENSP00000353151.5
HOXA3	ENST00000612286.5	c.-389-3421G>C		intron_variant		2	NM_153631.3	ENSP00000484411.1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 192 AN: 150284 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00251

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.00242

GnomAD3 exomes AF: 0.00152 AC: 23 AN: 15170 Hom.: 0 AF XY: 0.00151 AC XY: 13 AN XY: 8596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000240

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.00198 AC: 2235 AN: 1129430 Hom.: 1 Cov.: 39 AF XY: 0.00200 AC XY: 1086 AN XY: 543062

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.0000710

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000171

Gnomad4 NFE exome AF: 0.00224

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.00128 AC: 192 AN: 150392 Hom.: 0 Cov.: 34 AF XY: 0.00105 AC XY: 77 AN XY: 73434

Gnomad4 AFR AF: 0.000339

Gnomad4 AMR AF: 0.00251

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000101

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00149

ExAC AF: 0.000627 AC: 46

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

Apr 09, 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	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.87
DEOGEN2	Benign	0.052	T;T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.41	.;.;T
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.81	L;L;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.22	.;N;N
REVEL	Benign	0.089
Sift	Benign	0.32	.;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.90	P;P;P
Vest4		0.27
MutPred		0.17		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.52
MPC		0.63
ClinPred		0.039	T
GERP RS		-0.35
Varity_R		0.060
gMVP		0.16

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: rs761518289; hg19: chr7-27170110; COSMIC: COSV99073506; COSMIC: COSV99073506;