7-27184599-AGCCGCCGCC-AGCCGCC

Variant names:

• chr7-27184599-AGCC-A
• rs770195077
• NM_005523.6:c.543_545delGGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005523.6(HOXA11):​c.543_545delGGC​(p.Ala182del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,493,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: HOXA11 NM_005523.6 disruptive_inframe_deletion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.15
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 7-27184599-AGCC-A is Benign according to our data. Variant chr7-27184599-AGCC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3056914.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 10 AD gene.

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.543_545delGGC	p.Ala182del	disruptive_inframe_deletion	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.543_545delGGC	p.Ala182del	disruptive_inframe_deletion	Exon 1 of 2	ENSP00000006015.3	P31270
	HOXA11	ENST00000517402.1	TSL:1	c.450_452delGGC	p.Ala151del	disruptive_inframe_deletion	Exon 2 of 3	ENSP00000448962.1	H0YIA6
	HOXA11-AS	ENST00000520360.6	TSL:5	n.108_110delCGC		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000660 AC: 10 AN: 151516 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

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: 0.0000590

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00104 AC: 101 AN: 96890 AF XY: 0.000774

Gnomad AFR exome AF: 0.00216

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.000318

Gnomad EAS exome AF: 0.00290

Gnomad FIN exome AF: 0.000341

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.000331 AC: 444 AN: 1341826 Hom.: 0 AF XY: 0.000322 AC XY: 213 AN XY: 661786

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000364 AC: 10 AN: 27488

American (AMR) AF: 0.000741 AC: 21 AN: 28336

Ashkenazi Jewish (ASJ) AF: 0.000386 AC: 9 AN: 23318

East Asian (EAS) AF: 0.000414 AC: 13 AN: 31378

South Asian (SAS) AF: 0.000539 AC: 39 AN: 72364

European-Finnish (FIN) AF: 0.000192 AC: 9 AN: 46856

Middle Eastern (MID) AF: 0.000221 AC: 1 AN: 4530

European-Non Finnish (NFE) AF: 0.000301 AC: 317 AN: 1052242

Other (OTH) AF: 0.000452 AC: 25 AN: 55314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000660 AC: 10 AN: 151516 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73990

African (AFR) AF: 0.000145 AC: 6 AN: 41242

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67816

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HOXA11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=81/19	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: rs770195077; hg19: chr7-27224218; COSMIC: COSV104524288; COSMIC: COSV104524288;