7-27130315-A-G

Position:

• chr7-27130315-A-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.419T>C​(p.Leu140Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.965 in 1,086,266 control chromosomes in the GnomAD database, including 506,437 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 (66661 hom., cov: 35)
  • Exomes 𝑓: 0.97 (439776 hom.)
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.407

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=6.0331087E-7).
• BP6: Variant 7-27130315-A-G is Benign according to our data. Variant chr7-27130315-A-G is described in ClinVar as [Benign]. Clinvar id is 1231880.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXA4	NM_002141.5	c.419T>C	p.Leu140Pro	missense_variant	1/2	ENST00000360046.10	NP_002132.3
HOXA3	NM_153631.3	c.-389-3245T>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.419T>C	p.Leu140Pro	missense_variant	1/2	1	NM_002141.5	ENSP00000353151.5
HOXA3	ENST00000612286.5	c.-389-3245T>C		intron_variant		2	NM_153631.3	ENSP00000484411.1

Frequencies

GnomAD3 genomes AF: 0.950 AC: 140120 AN: 147570 Hom.: 66608 Cov.: 35

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.967

Gnomad AMR AF: 0.967

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.944

Gnomad FIN AF: 0.956

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.970

Gnomad OTH AF: 0.945

GnomAD3 exomes AF: 0.969 AC: 316 AN: 326 Hom.: 153 AF XY: 0.968 AC XY: 180 AN XY: 186

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.968

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 0.968 AC: 908540 AN: 938590 Hom.: 439776 Cov.: 36 AF XY: 0.968 AC XY: 424889 AN XY: 439112

Gnomad4 AFR exome AF: 0.899

Gnomad4 AMR exome AF: 0.963

Gnomad4 ASJ exome AF: 0.977

Gnomad4 EAS exome AF: 0.995

Gnomad4 SAS exome AF: 0.936

Gnomad4 FIN exome AF: 0.958

Gnomad4 NFE exome AF: 0.970

Gnomad4 OTH exome AF: 0.963

GnomAD4 genome AF: 0.950 AC: 140227 AN: 147676 Hom.: 66661 Cov.: 35 AF XY: 0.948 AC XY: 68167 AN XY: 71898

Gnomad4 AFR AF: 0.901

Gnomad4 AMR AF: 0.967

Gnomad4 ASJ AF: 0.982

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.944

Gnomad4 FIN AF: 0.956

Gnomad4 NFE AF: 0.970

Gnomad4 OTH AF: 0.946

Alfa AF: 0.961 Hom.: 10704

TwinsUK AF: 0.971 AC: 3601

ALSPAC AF: 0.973 AC: 3750

ExAC AF: 0.863 AC: 906

Asia WGS AF: 0.963 AC: 2675 AN: 2776

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.016	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.089	.;.;T
MetaRNN	Benign	6.0e-7	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	1.9	.;N;N
REVEL	Benign	0.26
Sift	Benign	0.23	.;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.036
MPC		0.83
ClinPred		0.029	T
GERP RS		0.23
Varity_R		0.068
gMVP		0.21

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: rs10251056; hg19: chr7-27169934; COSMIC: COSV57828121; COSMIC: COSV57828121;