rs35693898

Variant names:

• chr11-5226635-A-G
• rs35693898
• NM_000518.5:c.257T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000518.5(HBB):​c.257T>C​(p.Phe86Ser) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.979

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 11-5226635-A-G is Pathogenic according to our data. Variant chr11-5226635-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 15122.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.257T>C	p.Phe86Ser	missense_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.257T>C	p.Phe86Ser	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hemoglobinopathy Pathogenic:1

Sep 29, 1967

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

May 04, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Buenos Aires variant (HBB: c.257T>C; p.Phe86Ser, also known as Hb Bryn Mawr, and as Phe85Ser when numbered from the mature protein, rs35693898, HbVar ID: 414) is reported in the literature in heterozygous individuals affected with hemolytic anemia (see HbVar and references therein). The is variant is reported as unstable with increased oxygen affinity (see HbVar). This variant is reported in ClinVar (Variation ID: 15122) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The phenylalanine at codon 86 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.804). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;T;.;T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.67	.;T;T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.9	H;H;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.3	D;.;.;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0010	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.80		Gain of disorder (P = 0.0016);Gain of disorder (P = 0.0016);Gain of disorder (P = 0.0016);Gain of disorder (P = 0.0016);
MVP		0.86
MPC		0.30
ClinPred		0.97	D
GERP RS		-2.0
Varity_R		0.94
gMVP		0.99

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: rs35693898; hg19: chr11-5247865;