rs34628045

chr2-73448097-TCTC-Tchr2-73448097-TCTC-TCTCCTC

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):c.1574_1576del(p.Pro525del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,613,222 control chromosomes in the GnomAD database, including 114,241 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15344 hom., cov: 0)
  • Exomes 𝑓: 0.36 (98897 hom.)
• Consequence: ALMS1 NM_001378454.1 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.58

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001378454.1. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-73448097-TCTC-T is Benign according to our data. Variant chr2-73448097-TCTC-T is described in ClinVar as [Likely_benign]. Clinvar id is 210124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.1574_1576del	p.Pro525del	inframe_deletion	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.1577_1579del	p.Pro526del	inframe_deletion	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.1574_1576del	p.Pro525del	inframe_deletion	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65206 AN: 151534 Hom.: 15308 Cov.: 0

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.405

GnomAD4 exome AF: 0.363 AC: 531038 AN: 1461570 Hom.: 98897 AF XY: 0.363 AC XY: 263686 AN XY: 727106

Gnomad4 AFR exome AF: 0.654

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.369

Gnomad4 EAS exome AF: 0.245

Gnomad4 SAS exome AF: 0.335

Gnomad4 FIN exome AF: 0.367

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.431 AC: 65303 AN: 151652 Hom.: 15344 Cov.: 0 AF XY: 0.425 AC XY: 31473 AN XY: 74092

Gnomad4 AFR AF: 0.639

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.378

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.323

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.404

Alfa AF: 0.213 Hom.: 2755

Bravo AF: 0.438

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 22, 2023	The p.Pro525del variant in ALMS1 is classified as benign because it has been identified in 63.8% (26295/41186) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2019

- -

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: rs34628045; hg19: chr2-73675227;