4-8867547-G-A

Position:

• chr4-8867547-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018942.3(HMX1):​c.*146C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00854 in 1,184,266 control chromosomes in the GnomAD database, including 561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (352 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (209 hom.)
• Consequence: HMX1 NM_018942.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.11

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-8867547-G-A is Benign according to our data. Variant chr4-8867547-G-A is described in ClinVar as [Benign]. Clinvar id is 1276867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMX1	NM_018942.3	c.*146C>T		3_prime_UTR_variant	2/2	ENST00000400677.5	NP_061815.2
HMX1	NM_001306142.2	c.394+3674C>T		intron_variant			NP_001293071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMX1	ENST00000400677.5	c.*146C>T		3_prime_UTR_variant	2/2	1	NM_018942.3	ENSP00000383516	P1
HMX1	ENST00000506970.2	c.394+3674C>T		intron_variant		1		ENSP00000446997

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5610 AN: 152058 Hom.: 352 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0136

Gnomad SAS AF: 0.0388

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0291

GnomAD4 exome AF: 0.00435 AC: 4489 AN: 1032090 Hom.: 209 Cov.: 37 AF XY: 0.00424 AC XY: 2067 AN XY: 487048

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00867

Gnomad4 SAS exome AF: 0.0374

Gnomad4 FIN exome AF: 0.0000526

Gnomad4 NFE exome AF: 0.000254

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0370 AC: 5623 AN: 152176 Hom.: 352 Cov.: 33 AF XY: 0.0361 AC XY: 2684 AN XY: 74418

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0136

Gnomad4 SAS AF: 0.0382

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.0288

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.0404

Asia WGS AF: 0.0310 AC: 109 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.91

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: rs146878642; hg19: chr4-8869273;