rs35669628

chr11-5225635-G-Achr11-5225635-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000518.5(HBB):c.407C>T(p.Ala136Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A136D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

Genes affected

HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225635-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.37200397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.407C>T	p.Ala136Val	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.407C>T	p.Ala136Val	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.407C>T	p.Ala136Val	missense_variant	3/3			P1
HBB	ENST00000633227.1	c.*223C>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	3
HBB	ENST00000475226.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251362 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461742 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727204

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: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 01, 2023

Variant summary: HBB c.407C>T (p.Ala136Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251362 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.407C>T has been reported in the literature in at least one compound heterozygous individual affected with Hemoglobinopathy (e.g., Godbole_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a mildly decreased oxygen affinity (e.g., Zubriggen_2009). The following publications have been ascertained in the context of this evaluation (PMID: 29651865, 29365076, 19958196). No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Additionally, other missense variants have been reported in the literature in individuals affected with hemolytic anemia (c.406G>C (p.Ala136Pro) also known as Hb Altdorf) or silent hemoglobinopathies (c.407C>A (p.Ala136Asp), also known as Hb Beckman), and these other missense variants were found to be unstable and result in changes in oxygen affinity (PMIDs: 8450301, 1261680, 19453576, 26209877; Yucel_2013, no PMID)). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.65	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.057	T;.
Polyphen		0.090	B;B
Vest4		0.40
MutPred		0.38		Loss of disorder (P = 0.1535);Loss of disorder (P = 0.1535);
MVP		0.75
MPC		0.034
ClinPred		0.77	D
GERP RS		3.8
Varity_R		0.23
gMVP		0.81

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: rs35669628; hg19: chr11-5246865;