8-29009116-T-A

Position:

• chr8-29009116-T-A

Variant summary

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

The NM_001135726.3(HMBOX1):​c.631T>A​(p.Ser211Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 7.64

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=0.36687934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBOX1	NM_001135726.3	c.631T>A	p.Ser211Thr	missense_variant	5/10	ENST00000287701.15	NP_001129198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMBOX1	ENST00000287701.15	c.631T>A	p.Ser211Thr	missense_variant	5/10	1	NM_001135726.3	ENSP00000287701.10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Oct 01, 2024

The c.631T>A (p.S211T) alteration is located in exon 6 (coding exon 4) of the HMBOX1 gene. This alteration results from a T to A substitution at nucleotide position 631, causing the serine (S) at amino acid position 211 to be replaced by a threonine (T). 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	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Benign	0.49
DEOGEN2	Benign	0.28	T;.;T;.;T;.;.;.
Eigen	Benign	-0.046
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.7	L;L;.;.;L;.;.;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.58	N;N;N;N;N;N;.;N
REVEL	Uncertain	0.47
Sift	Benign	1.0	T;T;T;T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.037	B;B;.;.;B;B;B;P
Vest4		0.55
MutPred		0.25		Loss of disorder (P = 0.0664);Loss of disorder (P = 0.0664);Loss of disorder (P = 0.0664);Loss of disorder (P = 0.0664);Loss of disorder (P = 0.0664);Loss of disorder (P = 0.0664);Loss of disorder (P = 0.0664);Loss of disorder (P = 0.0664);
MVP		0.90
MPC		1.3
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.62

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: chr8-28866633;