10-92694685-G-A

Position:

• chr10-92694685-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002729.5(HHEX):​c.730G>A​(p.Glu244Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HHEX NM_002729.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

Genes affected

HHEX (HGNC:4901): (hematopoietically expressed homeobox) This gene encodes a member of the homeobox family of transcription factors, many of which are involved in developmental processes. Expression in specific hematopoietic lineages suggests that this protein may play a role in hematopoietic differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20905954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HHEX	NM_002729.5	c.730G>A	p.Glu244Lys	missense_variant	4/4	ENST00000282728.10	NP_002720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HHEX	ENST00000282728.10	c.730G>A	p.Glu244Lys	missense_variant	4/4	1	NM_002729.5	ENSP00000282728	P1
HHEX	ENST00000492654.3	c.214G>A	p.Glu72Lys	missense_variant	3/3	1		ENSP00000447953
HHEX	ENST00000472590.6	c.214G>A	p.Glu72Lys	missense_variant	4/4	2		ENSP00000450017

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2024

The c.730G>A (p.E244K) alteration is located in exon 4 (coding exon 4) of the HHEX gene. This alteration results from a G to A substitution at nucleotide position 730, causing the glutamic acid (E) at amino acid position 244 to be replaced by a lysine (K). 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	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T
Eigen	Benign	0.032
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.28	B;.;.
Vest4		0.20
MutPred		0.24		Gain of ubiquitination at E244 (P = 0.0069);.;.;
MVP		0.96
MPC		0.82
ClinPred		0.63	D
GERP RS		5.4
Varity_R		0.37
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-94454442;