chr7-27184550-C-G

Variant names:

• chr7-27184550-C-G
• rs991270582
• NM_005523.6:c.595G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005523.6(HOXA11):​c.595G>C​(p.Gly199Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000813 in 1,229,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. G199C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: HOXA11 NM_005523.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• Publications: 0 publications found

Genes affected

HOXA11 (HGNC:5101): (homeobox A11) 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. This gene is involved in the regulation of uterine development and is required for female fertility. Mutations in this gene can cause radio-ulnar synostosis with amegakaryocytic thrombocytopenia. [provided by RefSeq, Jul 2008]

HOXA11-AS (HGNC:24957): (HOXA11 antisense RNA) This gene produces a long non-coding RNA in antisense to transcription of the homeobox A11 gene. This transcript may associate with chromatin factors such as Polycomb repressive complex and act as a sponge for microRNAs, thereby participating in the regulation of expression of target genes. High levels of this transcript may be associated with tumor progression. [provided by RefSeq, Dec 2017]

ENSG00000293630 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16506675).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005523.6. 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
	HOXA11	NM_005523.6	MANE Select	c.595G>C	p.Gly199Arg	missense	Exon 1 of 2	NP_005514.1	P31270

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA11	ENST00000006015.4	TSL:1 MANE Select	c.595G>C	p.Gly199Arg	missense	Exon 1 of 2	ENSP00000006015.3	P31270
	HOXA11	ENST00000517402.1	TSL:1	c.502G>C	p.Gly168Arg	missense	Exon 2 of 3	ENSP00000448962.1	H0YIA6
	HOXA11-AS	ENST00000520360.6	TSL:5	n.44C>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.13e-7 AC: 1 AN: 1229998 Hom.: 0 Cov.: 28 AF XY: 0.00000164 AC XY: 1 AN XY: 608186

African (AFR) AF: 0.00 AC: 0 AN: 25180

American (AMR) AF: 0.00 AC: 0 AN: 26854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22292

East Asian (EAS) AF: 0.0000344 AC: 1 AN: 29058

South Asian (SAS) AF: 0.00 AC: 0 AN: 66220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3932

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 961706

Other (OTH) AF: 0.00 AC: 0 AN: 51070

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.12
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.25
Sift	Benign	0.48	T
Sift4G	Benign	0.20	T
Polyphen		0.62	P
Vest4		0.14
MutPred		0.33		Gain of methylation at G199 (P = 0.0237)
MVP		0.76
MPC		1.1
ClinPred		0.17	T
GERP RS		1.2
Varity_R		0.053
gMVP		0.50
Mutation Taster		=96/4	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: rs991270582; hg19: chr7-27224169;