rs34628045

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-73448097-TCTC-T
• chr2-73448097-TCTC-TCTCCTC

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

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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.1574_1576delCTC	p.Pro525del	disruptive_inframe_deletion	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.1574_1576delCTC	p.Pro525del	disruptive_inframe_deletion	Exon 8 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.1574_1576delCTC	p.Pro525del	disruptive_inframe_deletion	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.1448_1450delCTC	p.Pro483del	disruptive_inframe_deletion	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.1193_1195delCTC	p.Pro398del	disruptive_inframe_deletion	Exon 6 of 21	ENSP00000507421.1	A0A804HJA5

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;