chr16-177378-T-C

Position:

• chr16-177378-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000558.5(HBA1):​c.396T>C​(p.Ser132Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,613,822 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: HBA1 NM_000558.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -1.69

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-177378-T-C is Benign according to our data. Variant chr16-177378-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 439101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5	c.396T>C	p.Ser132Ser	synonymous_variant	3/3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.396T>C	p.Ser132Ser	synonymous_variant	3/3	1	NM_000558.5	ENSP00000322421.5
HBA1	ENST00000472694.1	n.532T>C		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1	c.300T>C	p.Ser100Ser	synonymous_variant	3/3	2		ENSP00000380899.1
ENSG00000290010	ENST00000702457.1	n.113A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000241 AC: 60 AN: 249398 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135252

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.000116

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: 0.000249

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000416 AC: 608 AN: 1461486 Hom.: 0 Cov.: 32 AF XY: 0.000373 AC XY: 271 AN XY: 727050

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000455

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000805 AC XY: 60 AN XY: 74492

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000556 Hom.: 0

Bravo AF: 0.000842

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 13, 2023	- -

alpha Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 09, 2017

- -

HBA1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.8
DANN	Benign	0.43

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: rs149264789; hg19: chr16-227377; COSMIC: COSV52265590; COSMIC: COSV52265590;