8-28970140-C-T

Variant summary

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

The NM_001135726.3(HMBOX1):c.121C>T(p.His41Tyr) 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: HMBOX1 NM_001135726.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71

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]

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=0.2146965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMBOX1	NM_001135726.3	c.121C>T	p.His41Tyr	missense_variant	3/10	ENST00000287701.15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMBOX1	ENST00000287701.15	c.121C>T	p.His41Tyr	missense_variant	3/10	1	NM_001135726.3	P4

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

Sep 28, 2022

The c.121C>T (p.H41Y) alteration is located in exon 4 (coding exon 2) of the HMBOX1 gene. This alteration results from a C to T substitution at nucleotide position 121, causing the histidine (H) at amino acid position 41 to be replaced by a tyrosine (Y). 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	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;T;.;T;.;T;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;.;.;N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.049	D;T;D;D;D;D;D;.;D
Sift4G	Benign	0.89	T;T;T;T;T;T;T;T;T
Polyphen		0.72	P;.;P;.;.;P;P;P;B
Vest4		0.44
MutPred		0.34		Loss of disorder (P = 0.0352);Loss of disorder (P = 0.0352);Loss of disorder (P = 0.0352);Loss of disorder (P = 0.0352);Loss of disorder (P = 0.0352);Loss of disorder (P = 0.0352);Loss of disorder (P = 0.0352);Loss of disorder (P = 0.0352);Loss of disorder (P = 0.0352);
MVP		0.27
MPC		0.47
ClinPred		0.37	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.36

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: rs1827140072; hg19: chr8-28827657;