8-28970135-C-G

Position:

• chr8-28970135-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001135726.3(HMBOX1):​c.116C>G​(p.Thr39Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMBOX1 NM_001135726.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32493287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBOX1	NM_001135726.3	c.116C>G	p.Thr39Ser	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.116C>G	p.Thr39Ser	missense_variant	3/10	1	NM_001135726.3	ENSP00000287701.10

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

Aug 05, 2024

The c.116C>G (p.T39S) alteration is located in exon 4 (coding exon 2) of the HMBOX1 gene. This alteration results from a C to G substitution at nucleotide position 116, causing the threonine (T) at amino acid position 39 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;D;.;T;.;T;.;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D;T;T;T;T;.;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.;M;.;.;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.1	N;D;N;N;N;N;N;.;N
REVEL	Benign	0.12
Sift	Benign	0.16	T;D;T;T;T;T;T;.;T
Sift4G	Uncertain	0.040	D;D;D;D;D;D;D;D;D
Polyphen		0.043	B;.;B;.;.;B;B;B;B
Vest4		0.58
MutPred		0.61		Gain of disorder (P = 0.0934);Gain of disorder (P = 0.0934);Gain of disorder (P = 0.0934);Gain of disorder (P = 0.0934);Gain of disorder (P = 0.0934);Gain of disorder (P = 0.0934);Gain of disorder (P = 0.0934);Gain of disorder (P = 0.0934);Gain of disorder (P = 0.0934);
MVP		0.44
MPC		0.28
ClinPred		0.52	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.51

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: chr8-28827652;