2-73385903-TGGAGGAGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr2-73385903-TGGA-T
• rs55889738
• NM_001378454.1:c.72_74delGGA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):​c.72_74delGGA​(p.Glu25del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 698,502 control chromosomes in the GnomAD database, including 613 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E24E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.055 (348 hom., cov: 0)
  • Exomes 𝑓: 0.034 (265 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 3.18
• Publications: 7 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000285068 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-TGGA-T is Benign according to our data. Variant chr2-73385903-TGGA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 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.72_74delGGA	p.Glu25del	disruptive_inframe_deletion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.72_74delGGA	p.Glu25del	disruptive_inframe_deletion	Exon 1 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.72_74delGGA	p.Glu25del	disruptive_inframe_deletion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.72_74delGGA	p.Glu25del	disruptive_inframe_deletion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.72_74delGGA	p.Glu25del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.0546 AC: 7831 AN: 143476 Hom.: 344 Cov.: 0

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.0170

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0316

Gnomad EAS AF: 0.0424

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.0458

Gnomad MID AF: 0.0142

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0450

GnomAD2 exomes AF: 0.0631 AC: 5258 AN: 83366 AF XY: 0.0545

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.0407

Gnomad FIN exome AF: 0.0392

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0560

GnomAD4 exome AF: 0.0343 AC: 19023 AN: 554922 Hom.: 265 AF XY: 0.0323 AC XY: 9565 AN XY: 296246

African (AFR) AF: 0.0885 AC: 1389 AN: 15688

American (AMR) AF: 0.155 AC: 4808 AN: 31096

Ashkenazi Jewish (ASJ) AF: 0.0327 AC: 572 AN: 17516

East Asian (EAS) AF: 0.0352 AC: 1075 AN: 30534

South Asian (SAS) AF: 0.0127 AC: 708 AN: 55622

European-Finnish (FIN) AF: 0.0403 AC: 1458 AN: 36146

Middle Eastern (MID) AF: 0.0166 AC: 40 AN: 2410

European-Non Finnish (NFE) AF: 0.0234 AC: 7860 AN: 335948

Other (OTH) AF: 0.0371 AC: 1113 AN: 29962

GnomAD4 genome AF: 0.0547 AC: 7850 AN: 143580 Hom.: 348 Cov.: 0 AF XY: 0.0555 AC XY: 3865 AN XY: 69632

African (AFR) AF: 0.0949 AC: 3791 AN: 39948

American (AMR) AF: 0.114 AC: 1669 AN: 14694

Ashkenazi Jewish (ASJ) AF: 0.0316 AC: 105 AN: 3322

East Asian (EAS) AF: 0.0423 AC: 194 AN: 4584

South Asian (SAS) AF: 0.0134 AC: 57 AN: 4262

European-Finnish (FIN) AF: 0.0458 AC: 430 AN: 9392

Middle Eastern (MID) AF: 0.0150 AC: 4 AN: 266

European-Non Finnish (NFE) AF: 0.0233 AC: 1496 AN: 64316

Other (OTH) AF: 0.0456 AC: 90 AN: 1972

Alfa AF: 0.0231 Hom.: 1022

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Alstrom syndrome (4)
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=75/25	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55889738; hg19: chr2-73613031; COSMIC: COSV105092295; COSMIC: COSV105092295;