rs121909818

Positions:

• chr11-5225714-C-G
• chr11-5225714-C-A
• chr11-5225714-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP5_Moderate BP4

The NM_000518.5(HBB):​c.328G>C​(p.Val110Leu) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V110M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -0.202

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 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 chr11-5225714-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 11-5225714-C-G is Pathogenic according to our data. Variant chr11-5225714-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 15230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37097627). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.328G>C	p.Val110Leu	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.328G>C	p.Val110Leu	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.328G>C	p.Val110Leu	missense_variant	3/3			P1
HBB	ENST00000475226.1	n.260G>C		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1	c.*144G>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Sep 04, 2019

Found in at least one patient with expected phenotype for this gene. Predicted to have a tolerated effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected and unaffected individuals from multiple families. -

HEMOGLOBIN JOHNSTOWN Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.20	N
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.0	N;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.076	T;.
Polyphen		0.14	B;B
Vest4		0.92
MutPred		0.65		Loss of methylation at R105 (P = 0.2842);Loss of methylation at R105 (P = 0.2842);
MVP		0.66
MPC		0.037
ClinPred		0.27	T
GERP RS		0.68
Varity_R		0.60
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33969677; hg19: chr11-5246944;