NM_006735.4:c.391+72G>C

Variant names:

• chr7-27102038-C-G
• rs2428431
• NM_006735.4:c.391+72G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006735.4(HOXA2):​c.391+72G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,580,634 control chromosomes in the GnomAD database, including 99,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.27 (7329 hom., cov: 31)
  • Exomes 𝑓: 0.35 (92111 hom.)
• Consequence: HOXA2 NM_006735.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.520
• Publications: 11 publications found

Genes affected

HOXA2 (HGNC:5103): (homeobox A2) 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. The encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development. [provided by RefSeq, Jul 2008]

HOXA2 Gene-Disease associations (from GenCC):

• bilateral microtia-deafness-cleft palate syndrome

  Inheritance: AD, AR, SD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine
• microtia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000293629 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-27102038-C-G is Benign according to our data. Variant chr7-27102038-C-G is described in ClinVar as Benign. ClinVar VariationId is 1289147.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006735.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA2	NM_006735.4	MANE Select	c.391+72G>C		intron	N/A	NP_006726.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOXA2	ENST00000222718.7	TSL:1 MANE Select	c.391+72G>C		intron	N/A	ENSP00000222718.5
	HOXA2	ENST00000612779.1	TSL:6	n.649G>C		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000293629	ENST00000716605.1		n.310+5650C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41740 AN: 151958 Hom.: 7330 Cov.: 31

Gnomad AFR AF: 0.0683

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.298

GnomAD2 exomes AF: 0.320 AC: 64969 AN: 202938 AF XY: 0.319

Gnomad AFR exome AF: 0.0523

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.434

Gnomad EAS exome AF: 0.0968

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.352 AC: 502310 AN: 1428558 Hom.: 92111 Cov.: 29 AF XY: 0.349 AC XY: 247565 AN XY: 709180

African (AFR) AF: 0.0536 AC: 1772 AN: 33058

American (AMR) AF: 0.384 AC: 16077 AN: 41898

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 10985 AN: 25488

East Asian (EAS) AF: 0.0937 AC: 3656 AN: 39012

South Asian (SAS) AF: 0.262 AC: 21748 AN: 82930

European-Finnish (FIN) AF: 0.371 AC: 16255 AN: 43792

Middle Eastern (MID) AF: 0.372 AC: 2126 AN: 5714

European-Non Finnish (NFE) AF: 0.373 AC: 409662 AN: 1097402

Other (OTH) AF: 0.338 AC: 20029 AN: 59264

GnomAD4 genome AF: 0.274 AC: 41736 AN: 152076 Hom.: 7329 Cov.: 31 AF XY: 0.276 AC XY: 20554 AN XY: 74350

African (AFR) AF: 0.0681 AC: 2828 AN: 41506

American (AMR) AF: 0.348 AC: 5316 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3468

East Asian (EAS) AF: 0.100 AC: 519 AN: 5166

South Asian (SAS) AF: 0.265 AC: 1272 AN: 4806

European-Finnish (FIN) AF: 0.376 AC: 3968 AN: 10566

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.372 AC: 25301 AN: 67956

Other (OTH) AF: 0.295 AC: 623 AN: 2110

Alfa AF: 0.283 Hom.: 1287

Bravo AF: 0.262

Asia WGS AF: 0.181 AC: 633 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.41
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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: rs2428431; hg19: chr7-27141657; COSMIC: COSV56066185; COSMIC: COSV56066185;