1-158611131-GCACACA-G

Position:

• chr1-158611131-GCACACA-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS1_Supporting BS2_Supporting

The NM_003126.4(SPTA1):​c.*127_*132delTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00769 in 667,742 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0087 (2 hom.)
• Consequence: SPTA1 NM_003126.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.117

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 Likely_benign. Variant got -2 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00874 (4579/523842) while in subpopulation AFR AF= 0.0228 (339/14888). AF 95% confidence interval is 0.0208. There are 2 homozygotes in gnomad4_exome. There are 2395 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTA1	NM_003126.4	c.*127_*132delTGTGTG		3_prime_UTR_variant	52/52	ENST00000643759.2	NP_003117.2
OR10Z1	NM_001004478.2	c.*3781_*3786delACACAC		3_prime_UTR_variant	2/2	ENST00000641002.1	NP_001004478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759	c.*127_*132delTGTGTG		3_prime_UTR_variant	52/52		NM_003126.4	ENSP00000495214.1
OR10Z1	ENST00000641002.1	c.*3781_*3786delACACAC		3_prime_UTR_variant	2/2		NM_001004478.2	ENSP00000493003.1

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 553 AN: 143792 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00968

Gnomad SAS AF: 0.00406

Gnomad FIN AF: 0.000218

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00224

Gnomad OTH AF: 0.00307

GnomAD4 exome AF: 0.00874 AC: 4579 AN: 523842 Hom.: 2 AF XY: 0.00861 AC XY: 2395 AN XY: 278078

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.00777

Gnomad4 ASJ exome AF: 0.00953

Gnomad4 EAS exome AF: 0.0163

Gnomad4 SAS exome AF: 0.00786

Gnomad4 FIN exome AF: 0.00469

Gnomad4 NFE exome AF: 0.00796

Gnomad4 OTH exome AF: 0.00997

GnomAD4 genome AF: 0.00386 AC: 556 AN: 143900 Hom.: 1 Cov.: 0 AF XY: 0.00394 AC XY: 274 AN XY: 69564

Gnomad4 AFR AF: 0.00795

Gnomad4 AMR AF: 0.00202

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00970

Gnomad4 SAS AF: 0.00407

Gnomad4 FIN AF: 0.000218

Gnomad4 NFE AF: 0.00224

Gnomad4 OTH AF: 0.00304

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Elliptocytosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Pyropoikilocytosis, hereditary Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spherocytosis, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55832242; hg19: chr1-158580921;