8-28970443-A-G

Position:

• chr8-28970443-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001135726.3(HMBOX1):​c.424A>G​(p.Met142Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HMBOX1 NM_001135726.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

HMBOX1 (HGNC:26137): (homeobox containing 1) Enables double-stranded telomeric DNA binding activity; identical protein binding activity; and sequence-specific double-stranded DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II; positive regulation of telomerase activity; and positive regulation of telomere maintenance via telomerase. Located in several cellular components, including centrosome; chromosome, telomeric region; and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

HMBOX1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035798967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBOX1	NM_001135726.3	c.424A>G	p.Met142Val	missense_variant	3/10	ENST00000287701.15	NP_001129198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBOX1	ENST00000287701.15	c.424A>G	p.Met142Val	missense_variant	3/10	1	NM_001135726.3	ENSP00000287701.10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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

Jun 25, 2024

The c.424A>G (p.M142V) alteration is located in exon 4 (coding exon 2) of the HMBOX1 gene. This alteration results from a A to G substitution at nucleotide position 424, causing the methionine (M) at amino acid position 142 to be replaced by a valine (V). 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	0.052
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Benign	0.61
DEOGEN2	Benign	0.28	T;.;T;.;T;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;.;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.036	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	-1.8	N;N;.;.;N;.;.;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.33	N;N;N;N;N;N;.;N
REVEL	Benign	0.28
Sift	Benign	0.95	T;T;T;T;T;T;.;T
Sift4G	Benign	0.74	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;B;B;B;B
Vest4		0.19
MutPred		0.17		Loss of MoRF binding (P = 0.1167);Loss of MoRF binding (P = 0.1167);Loss of MoRF binding (P = 0.1167);Loss of MoRF binding (P = 0.1167);Loss of MoRF binding (P = 0.1167);Loss of MoRF binding (P = 0.1167);Loss of MoRF binding (P = 0.1167);Loss of MoRF binding (P = 0.1167);
MVP		0.45
MPC		0.25
ClinPred		0.072	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.22

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: rs111980547; hg19: chr8-28827960;