chr7-27130517-A-T

Variant names:

• chr7-27130517-A-T
• rs765734275
• NM_002141.5:c.217T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002141.5(HOXA4):​c.217T>A​(p.Tyr73Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000666 in 150,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y73H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HOXA4 NM_002141.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 0 publications found

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:):

HOXA-AS3 (HGNC:43748): (HOXA cluster antisense RNA 3)

HOXA-AS2 (HGNC:43745): (HOXA cluster antisense RNA 2) This gene produces a long non-coding RNA that promotes cell proliferation. This transcript may interact with enhancer of zeste homolog 2 Polycomb repressive complex to repress gene expression. [provided by RefSeq, Dec 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39982343).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002141.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA4	NM_002141.5	MANE Select	c.217T>A	p.Tyr73Asn	missense	Exon 1 of 2	NP_002132.3
	HOXA3	NM_153631.3	MANE Select	c.-389-3447T>A		intron	N/A	NP_705895.1	O43365
	HOXA3	NM_001384335.1		c.-505-3447T>A		intron	N/A	NP_001371264.1	O43365

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA4	ENST00000360046.10	TSL:1 MANE Select	c.217T>A	p.Tyr73Asn	missense	Exon 1 of 2	ENSP00000353151.5	Q00056
	HOXA4	ENST00000610970.1	TSL:1	c.217T>A	p.Tyr73Asn	missense	Exon 1 of 2	ENSP00000479166.1	Q00056
	HOXA3	ENST00000612286.5	TSL:2 MANE Select	c.-389-3447T>A		intron	N/A	ENSP00000484411.1	O43365

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150122 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1179392 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 572406

African (AFR) AF: 0.00 AC: 0 AN: 23130

American (AMR) AF: 0.00 AC: 0 AN: 13310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15998

East Asian (EAS) AF: 0.00 AC: 0 AN: 25294

South Asian (SAS) AF: 0.00 AC: 0 AN: 42920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 971042

Other (OTH) AF: 0.00 AC: 0 AN: 47182

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150230 Hom.: 0 Cov.: 34 AF XY: 0.0000136 AC XY: 1 AN XY: 73366

African (AFR) AF: 0.00 AC: 0 AN: 41242

American (AMR) AF: 0.00 AC: 0 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67354

Other (OTH) AF: 0.00 AC: 0 AN: 2084

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.031
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.13
Sift	Benign	0.051	T
Sift4G	Uncertain	0.031	D
Polyphen		0.68	P
Vest4		0.48
MutPred		0.32		Gain of relative solvent accessibility (P = 0.005)
MVP		0.87
MPC		1.3
ClinPred		0.69	D
GERP RS		3.6
PromoterAI		-0.044	Neutral
Varity_R		0.19
gMVP		0.65
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs765734275; hg19: chr7-27170136;