chr4-8867639-C-T

Variant names:

• chr4-8867639-C-T
• rs7293298
• NM_018942.3:c.*54G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.46
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• oculoauricular syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018942.3. 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
	HMX1	NM_018942.3	MANE Select	c.*54G>A		3_prime_UTR	Exon 2 of 2	NP_061815.2	Q9NP08
	HMX1	NM_001306142.2		c.394+3582G>A		intron	N/A	NP_001293071.1	F1T0J4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMX1	ENST00000400677.5	TSL:1 MANE Select	c.*54G>A		3_prime_UTR	Exon 2 of 2	ENSP00000383516.3	Q9NP08
	HMX1	ENST00000506970.2	TSL:1	c.394+3582G>A		intron	N/A	ENSP00000446997.2	F1T0J4

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9866 AN: 152124 Hom.: 1061 Cov.: 33

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.: 37 AF XY: 0.00665 AC XY: 3329 AN XY: 500636

African (AFR) AF: 0.229 AC: 5027 AN: 21976

American (AMR) AF: 0.0221 AC: 170 AN: 7704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13392

East Asian (EAS) AF: 0.00839 AC: 209 AN: 24904

South Asian (SAS) AF: 0.0374 AC: 728 AN: 19472

European-Finnish (FIN) AF: 0.0000489 AC: 1 AN: 20460

Middle Eastern (MID) AF: 0.0141 AC: 47 AN: 3334

European-Non Finnish (NFE) AF: 0.000323 AC: 293 AN: 907050

Other (OTH) AF: 0.0196 AC: 826 AN: 42104

GnomAD4 genome AF: 0.0649 AC: 9886 AN: 152240 Hom.: 1064 Cov.: 33 AF XY: 0.0626 AC XY: 4659 AN XY: 74428

African (AFR) AF: 0.220 AC: 9137 AN: 41522

American (AMR) AF: 0.0220 AC: 337 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0136 AC: 70 AN: 5160

South Asian (SAS) AF: 0.0389 AC: 188 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68022

Other (OTH) AF: 0.0468 AC: 99 AN: 2116

Alfa AF: 0.0376 Hom.: 74

Bravo AF: 0.0720

Asia WGS AF: 0.0360 AC: 124 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.65
DANN	Benign	0.83
PhyloP100		-2.5
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: rs7293298; hg19: chr4-8869365; COSMIC: COSV108244354;