1-158610969-G-A

Variant names:

• chr1-158610969-G-A
• rs12601
• NM_003126.4:c.*295C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003126.4(SPTA1):​c.*295C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 309,906 control chromosomes in the GnomAD database, including 44,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21092 hom., cov: 31)
  • Exomes 𝑓: 0.53 (22967 hom.)
• Consequence: SPTA1 NM_003126.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.104

Genes affected

SPTA1 (HGNC:11272): (spectrin alpha, erythrocytic 1) This gene encodes a member of a family of molecular scaffold proteins that link the plasma membrane to the actin cytoskeleton and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. The encoded protein is primarily composed of 22 spectrin repeats which are involved in dimer formation. It forms a component of the erythrocyte plasma membrane. Mutations in this gene result in a variety of hereditary red blood cell disorders, including elliptocytosis-2, pyropoikilocytosis, and spherocytosis, type 3. [provided by RefSeq, Aug 2017]

OR10Z1 (HGNC:14996): (olfactory receptor family 10 subfamily Z member 1) Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-158610969-G-A is Benign according to our data. Variant chr1-158610969-G-A is described in ClinVar as [Benign]. Clinvar id is 292920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.*295C>T		3_prime_UTR_variant	Exon 52 of 52	ENST00000643759.2	NP_003117.2
OR10Z1	NM_001004478.2	c.*3589G>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000641002.1	NP_001004478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759	c.*295C>T		3_prime_UTR_variant	Exon 52 of 52		NM_003126.4	ENSP00000495214.1
OR10Z1	ENST00000641002.1	c.*3589G>A		3_prime_UTR_variant	Exon 2 of 2		NM_001004478.2	ENSP00000493003.1
SPTA1	ENST00000485680.1	n.*239C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79215 AN: 151738 Hom.: 21066 Cov.: 31

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.537

GnomAD4 exome AF: 0.533 AC: 84218 AN: 158050 Hom.: 22967 Cov.: 2 AF XY: 0.524 AC XY: 43938 AN XY: 83832

Gnomad4 AFR exome AF: 0.411

Gnomad4 AMR exome AF: 0.529

Gnomad4 ASJ exome AF: 0.568

Gnomad4 EAS exome AF: 0.597

Gnomad4 SAS exome AF: 0.420

Gnomad4 FIN exome AF: 0.613

Gnomad4 NFE exome AF: 0.548

Gnomad4 OTH exome AF: 0.547

GnomAD4 genome AF: 0.522 AC: 79290 AN: 151856 Hom.: 21092 Cov.: 31 AF XY: 0.528 AC XY: 39182 AN XY: 74182

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.544

Gnomad4 ASJ AF: 0.570

Gnomad4 EAS AF: 0.625

Gnomad4 SAS AF: 0.435

Gnomad4 FIN AF: 0.639

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.542

Alfa AF: 0.541 Hom.: 10432

Bravo AF: 0.515

Asia WGS AF: 0.558 AC: 1940 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Elliptocytosis 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary spherocytosis type 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pyropoikilocytosis, hereditary Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.0
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs12601; hg19: chr1-158580759;