4-8867719-G-A

Variant names:

• chr4-8867719-G-A
• rs1373277121
• NM_018942.3:c.1021C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_018942.3(HMX1):​c.1021C>T​(p.Arg341Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000443 in 1,127,424 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R341P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: HMX1 NM_018942.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0810

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMX1	NM_018942.3	c.1021C>T	p.Arg341Trp	missense_variant	Exon 2 of 2	ENST00000400677.5	NP_061815.2
HMX1	NM_001306142.2	c.394+3502C>T		intron_variant	Intron 1 of 1		NP_001293071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMX1	ENST00000400677.5	c.1021C>T	p.Arg341Trp	missense_variant	Exon 2 of 2	1	NM_018942.3	ENSP00000383516.3
HMX1	ENST00000506970.2	c.394+3502C>T		intron_variant	Intron 1 of 1	1		ENSP00000446997.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000443 AC: 5 AN: 1127424 Hom.: 0 Cov.: 37 AF XY: 0.00000923 AC XY: 5 AN XY: 541816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000334

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000316

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1021C>T (p.R341W) alteration is located in exon 2 (coding exon 2) of the HMX1 gene. This alteration results from a C to T substitution at nucleotide position 1021, causing the arginine (R) at amino acid position 341 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.11
Eigen_PC	Benign	0.059
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.48		Gain of catalytic residue at M344 (P = 0.0011);
MVP		0.90
MPC		2.0
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.44
gMVP		0.41

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: rs1373277121; hg19: chr4-8869445; COSMIC: COSV68771501;