8-28970056-A-T

Position:

• chr8-28970056-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001135726.3(HMBOX1):​c.37A>T​(p.Met13Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMBOX1 NM_001135726.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.54

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBOX1	NM_001135726.3	c.37A>T	p.Met13Leu	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.37A>T	p.Met13Leu	missense_variant	3/10	1	NM_001135726.3	ENSP00000287701.10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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 07, 2024

The c.37A>T (p.M13L) alteration is located in exon 4 (coding exon 2) of the HMBOX1 gene. This alteration results from a A to T substitution at nucleotide position 37, causing the methionine (M) at amino acid position 13 to be replaced by a leucine (L). 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	0.43
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T;T;.;T;.;T;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	L;.;L;.;.;L;.;.;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.84	N;N;N;N;N;N;N;.;N
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.70	P;.;P;.;.;P;P;P;P
Vest4		0.52
MutPred		0.70		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.86
MPC		0.23
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.83
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr8-28827573;