4-8867621-C-G

Position:

• chr4-8867621-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018942.3(HMX1):​c.*72G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,201,994 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (8 hom., cov: 33)
  • Exomes 𝑓: 0.012 (85 hom.)
• Consequence: HMX1 NM_018942.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.129

Genes affected

HMX1 (HGNC:5017): (H6 family homeobox 1) This gene encodes a transcription factor that belongs to the H6 family of homeobox proteins. This protein can bind a 5'-CAAG-3' core DNA sequence, and it is involved in the development of craniofacial structures. Mutations in this gene cause oculoauricular syndrome, a disorder of the eye and external ear. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-8867621-C-G is Benign according to our data. Variant chr4-8867621-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1206465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1165 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMX1	NM_018942.3	c.*72G>C		3_prime_UTR_variant	2/2	ENST00000400677.5	NP_061815.2
HMX1	NM_001306142.2	c.394+3600G>C		intron_variant			NP_001293071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMX1	ENST00000400677.5	c.*72G>C		3_prime_UTR_variant	2/2	1	NM_018942.3	ENSP00000383516	P1
HMX1	ENST00000506970.2	c.394+3600G>C		intron_variant		1		ENSP00000446997

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1165 AN: 152144 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00955

GnomAD4 exome AF: 0.0118 AC: 12356 AN: 1049734 Hom.: 85 Cov.: 37 AF XY: 0.0118 AC XY: 5861 AN XY: 495548

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00864

Gnomad4 ASJ exome AF: 0.0213

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00424

Gnomad4 FIN exome AF: 0.00478

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152260 Hom.: 8 Cov.: 33 AF XY: 0.00712 AC XY: 530 AN XY: 74438

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00864 Hom.: 1

Bravo AF: 0.00774

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.46

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: rs182509379; hg19: chr4-8869347;