Genetic Variant HMX1:c.*54G>A (chr4-8867639-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018942.3(HMX1):c.*54G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,212,636 control chromosomes in the GnomAD database, including 1,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 1064 hom., cov: 33)

Exomes 𝑓: 0.0069 ( 623 hom. )

Consequence

HMX1
NM_018942.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.46

Variant links:

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]

HMX1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 4-8867639-C-T is Benign according to our data. Variant chr4-8867639-C-T is described in ClinVar as [Benign]. Clinvar id is 1271782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMX1	NM_018942.3 link	c.*54G>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000400677.5	NP_061815.2	Q9NP08
HMX1	NM_001306142.2 link	c.394+3582G>A		intron_variant	Intron 1 of 1		NP_001293071.1	Q9NP08F1T0J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMX1	ENST00000400677 link	c.*54G>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_018942.3	ENSP00000383516.3		Q9NP08
HMX1	ENST00000506970.2 link	c.394+3582G>A		intron_variant	Intron 1 of 1	1		ENSP00000446997.2		F1T0J4

Frequencies

GnomAD3 genomes

AF:

0.0649

AC:

9866

AN:

152124

Hom.:

1061

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0135

Gnomad SAS

AF:

0.0397

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0473

GnomAD4 exome

AF:

0.00689

AC:

7301

AN:

1060396

Hom.:

623

Cov.:

AF XY:

0.00665

AC XY:

3329

AN XY:

500636

show subpopulations

Gnomad4 AFR exome

AF:

0.229

Gnomad4 AMR exome

AF:

0.0221

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00839

Gnomad4 SAS exome

AF:

0.0374

Gnomad4 FIN exome

AF:

0.0000489

Gnomad4 NFE exome

AF:

0.000323

Gnomad4 OTH exome

AF:

0.0196

GnomAD4 genome

AF:

0.0649

AC:

9886

AN:

152240

Hom.:

1064

Cov.:

AF XY:

0.0626

AC XY:

4659

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.220

Gnomad4 AMR

AF:

0.0220

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0136

Gnomad4 SAS

AF:

0.0389

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.0468

Alfa

AF:

0.0376

Hom.:

Bravo

AF:

0.0720

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.65

DANN

Benign

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over