Variant chr16-176931-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5PP3_Strong

The NM_000558.5(HBA1):c.98T>C(p.Met33Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M33K) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.31

Variant links:

Genes affected

HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) 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'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]

HBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-176931-T-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5 linkuse as main transcript	c.98T>C	p.Met33Thr	missense_variant, splice_region_variant	2/3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HBA1	ENST00000320868.9 linkuse as main transcript	c.98T>C	p.Met33Thr	missense_variant, splice_region_variant	2/3	1	NM_000558.5	ENSP00000322421	P1
HBA1	ENST00000472694.1 linkuse as main transcript	n.234T>C		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1 linkuse as main transcript	n.67T>C		splice_region_variant, non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost, splice_region_variant	2/3	2		ENSP00000380899

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148838

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000250

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000770

AC:

AN:

129824

Hom.:

AF XY:

0.0000142

AC XY:

AN XY:

70286

show subpopulations

Gnomad AFR exome

AF:

0.000141

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000433

AC:

AN:

924506

Hom.:

Cov.:

AF XY:

0.00000422

AC XY:

AN XY:

473620

show subpopulations

Gnomad4 AFR exome

AF:

0.0000450

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:

0.00000459

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000672

AC:

AN:

148838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72572

show subpopulations

Gnomad4 AFR

AF:

0.0000250

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

0.0027

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.24

T;.

Eigen

Uncertain

0.44

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.65

T;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

0.41

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.1

N;D

REVEL

Uncertain

0.64

Sift

Benign

0.14

T;D

Sift4G

Benign

0.19

T;D

Vest4

0.53

MutPred

0.79

Loss of stability (P = 0.0012);.;

MVP

0.90

ClinPred

0.035

GERP RS

0.77

Varity_R

0.54

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over