16-166016-C-A

Position:

• chr16-166016-C-A

Variant summary

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

The NM_001003938.4(HBM):​c.19C>A​(p.Arg7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBM NM_001003938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.263

Genes affected

HBM (HGNC:4826): (hemoglobin subunit mu) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. This gene has an ORF encoding a 141 aa polypeptide which is similar to the delta globins found in reptiles and birds. This locus was originally described as a pseudogene; however, it is currently thought to be a protein-coding gene. [provided by RefSeq, Jul 2008]

HBM (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBM	NM_001003938.4	c.19C>A	p.Arg7Ser	missense_variant	1/3	ENST00000356815.4	NP_001003938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBM	ENST00000356815.4	c.19C>A	p.Arg7Ser	missense_variant	1/3	1	NM_001003938.4	ENSP00000349270.3
HBM	ENST00000472539.5	n.206-252C>A		intron_variant		5
HBM	ENST00000496585.1	n.206-252C>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1439114 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

Jul 16, 2024

The c.19C>A (p.R7S) alteration is located in exon 1 (coding exon 1) of the HBM gene. This alteration results from a C to A substitution at nucleotide position 19, causing the arginine (R) at amino acid position 7 to be replaced by a serine (S). 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	0.42
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.92	P
Vest4		0.48
MutPred		0.65		Gain of glycosylation at R7 (P = 0.0338);
MVP		0.92
MPC		0.58
ClinPred		0.76	D
GERP RS		1.3
Varity_R		0.40
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1437861967; hg19: chr16-216015; COSMIC: COSV100720796; COSMIC: COSV100720796;