11-5225715-G-C

Position:

• chr11-5225715-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_000518.5(HBB):​c.327C>G​(p.Asn109Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N109?) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.625

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.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 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 chr11-5225716-T-C is described in Lovd as [Pathogenic].
• PP5: Variant 11-5225715-G-C is Pathogenic according to our data. Variant chr11-5225715-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3336287.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.327C>G	p.Asn109Lys	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.327C>G	p.Asn109Lys	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.327C>G	p.Asn109Lys	missense_variant	3/3			P1
HBB	ENST00000475226.1	n.259C>G		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1	c.*143C>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.31	N
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0090	D;.
Sift4G	Benign	0.094	T;.
Polyphen		0.47	P;P
Vest4		0.45
MutPred		0.77		Gain of methylation at N109 (P = 0.0283);Gain of methylation at N109 (P = 0.0283);
MVP		0.87
MPC		0.073
ClinPred		0.87	D
GERP RS		-3.5
Varity_R		0.48
gMVP		0.92

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: rs34933751; hg19: chr11-5246945;