16-154386-G-C

Position:

• chr16-154386-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005332.3(HBZ):​c.415G>C​(p.Glu139Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000582 in 1,374,054 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 30)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: HBZ NM_005332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

Genes affected

HBZ (HGNC:4835): (hemoglobin subunit zeta) Zeta-globin is an alpha-like hemoglobin. The zeta-globin polypeptide is synthesized in the yolk sac of the early embryo, while alpha-globin is produced throughout fetal and adult life. The zeta-globin gene is a member of the human alpha-globin gene cluster that includes five functional genes and two pseudogenes. The order of genes is: 5' - zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 -alpha-1 - theta1 - 3'. [provided by RefSeq, Nov 2009]

HBM (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25696775).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBZ	NM_005332.3	c.415G>C	p.Glu139Gln	missense_variant	3/3	ENST00000252951.3	NP_005323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBZ	ENST00000252951.3	c.415G>C	p.Glu139Gln	missense_variant	3/3	1	NM_005332.3	ENSP00000252951.2
HBM	ENST00000472539.5	n.205+290G>C		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000582 AC: 8 AN: 1374054 Hom.: 0 Cov.: 29 AF XY: 0.00000443 AC XY: 3 AN XY: 677214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000290

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000470

Gnomad4 OTH exome AF: 0.0000354

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

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

Jun 25, 2024

The c.415G>C (p.E139Q) alteration is located in exon 3 (coding exon 3) of the HBZ gene. This alteration results from a G to C substitution at nucleotide position 415, causing the glutamic acid (E) at amino acid position 139 to be replaced by a glutamine (Q). 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	0.16
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.093
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.058	T
Polyphen		0.72	P
Vest4		0.11
MutPred		0.40		Gain of MoRF binding (P = 0.0046);
MVP		0.97
MPC		0.083
ClinPred		0.87	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.34
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1001995715; hg19: chr16-204385;