8-28970380-A-G

Position:

• chr8-28970380-A-G

Variant summary

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

The NM_001135726.3(HMBOX1):​c.361A>G​(p.Asn121Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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: 3.13

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097254395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMBOX1	NM_001135726.3	c.361A>G	p.Asn121Asp	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.361A>G	p.Asn121Asp	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

Apr 29, 2024

The c.361A>G (p.N121D) 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 361, causing the asparagine (N) at amino acid position 121 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;T;.;T;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;.;D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.097	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.;.;N;.;.;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.83	N;N;N;N;N;N;.;N
REVEL	Benign	0.036
Sift	Benign	0.69	T;T;T;T;T;T;.;T
Sift4G	Benign	0.88	T;T;T;T;T;T;T;T
Polyphen		0.0090	B;B;.;.;B;B;B;B
Vest4		0.18
MutPred		0.27		Loss of MoRF binding (P = 0.049);Loss of MoRF binding (P = 0.049);Loss of MoRF binding (P = 0.049);Loss of MoRF binding (P = 0.049);Loss of MoRF binding (P = 0.049);Loss of MoRF binding (P = 0.049);Loss of MoRF binding (P = 0.049);Loss of MoRF binding (P = 0.049);
MVP		0.56
MPC		0.30
ClinPred		0.69	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.13

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: chr8-28827897;