chr2-73448097-TCTC-T

Variant names:

• chr2-73448097-TCTC-T
• rs34628045
• NM_001378454.1:c.1574_1576delCTC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):​c.1574_1576delCTC​(p.Pro525del) variant causes a disruptive 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 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.58
• Publications: 18 publications found

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]

ALMS1 Gene-Disease associations (from GenCC):

• Alstrom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ENSG00000295621 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.1574_1576delCTC	p.Pro525del	disruptive_inframe_deletion	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.1574_1576delCTC	p.Pro525del	disruptive_inframe_deletion	Exon 8 of 23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.1574_1576delCTC	p.Pro525del	disruptive_inframe_deletion	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1

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

African (AFR) AF: 0.654 AC: 21876 AN: 33468

American (AMR) AF: 0.281 AC: 12561 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 9637 AN: 26132

East Asian (EAS) AF: 0.245 AC: 9705 AN: 39692

South Asian (SAS) AF: 0.335 AC: 28857 AN: 86252

European-Finnish (FIN) AF: 0.367 AC: 19583 AN: 53412

Middle Eastern (MID) AF: 0.371 AC: 2137 AN: 5766

European-Non Finnish (NFE) AF: 0.364 AC: 405051 AN: 1111778

Other (OTH) AF: 0.358 AC: 21631 AN: 60378

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

African (AFR) AF: 0.639 AC: 26393 AN: 41308

American (AMR) AF: 0.335 AC: 5113 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1311 AN: 3466

East Asian (EAS) AF: 0.229 AC: 1181 AN: 5148

South Asian (SAS) AF: 0.323 AC: 1557 AN: 4816

European-Finnish (FIN) AF: 0.369 AC: 3875 AN: 10514

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.363 AC: 24652 AN: 67848

Other (OTH) AF: 0.404 AC: 853 AN: 2110

Alfa AF: 0.213 Hom.: 2755

Bravo AF: 0.438

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 22, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

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

Other links and lift over

dbSNP: rs34628045; hg19: chr2-73675227; COSMIC: COSV108055480; COSMIC: COSV108055480;