2-73385903-TGGAGGAGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGA

Variant names:

• chr2-73385903-TGGAGGAGGAGGAGGAGGA-T
• rs55889738
• NM_001378454.1:c.57_74delGGAGGAGGAGGAGGAGGA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_001378454.1(ALMS1):​c.57_74delGGAGGAGGAGGAGGAGGA​(p.Glu20_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 0.00131 in 701,364 control chromosomes in the GnomAD database, including 4 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E19del) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.45
• 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-TGGAGGAGGAGGAGGAGGA-T is Benign according to our data. Variant chr2-73385903-TGGAGGAGGAGGAGGAGGA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1676370.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00114 (164/143636) while in subpopulation NFE AF = 0.00109 (70/64334). AF 95% confidence interval is 0.000883. There are 1 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.57_74delGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.57_74delGGAGGAGGAGGAGGAGGA	p.Glu20_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.57_74delGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.57_74delGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25del	disruptive_inframe_deletion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.57_74delGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 164 AN: 143532 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00862

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00135 AC: 754 AN: 557728 Hom.: 3 AF XY: 0.00131 AC XY: 391 AN XY: 297826

African (AFR) AF: 0.000570 AC: 9 AN: 15784

American (AMR) AF: 0.000192 AC: 6 AN: 31236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17646

East Asian (EAS) AF: 0.000130 AC: 4 AN: 30668

South Asian (SAS) AF: 0.000107 AC: 6 AN: 55946

European-Finnish (FIN) AF: 0.00870 AC: 316 AN: 36320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2422

European-Non Finnish (NFE) AF: 0.00116 AC: 392 AN: 337586

Other (OTH) AF: 0.000697 AC: 21 AN: 30120

GnomAD4 genome AF: 0.00114 AC: 164 AN: 143636 Hom.: 1 Cov.: 0 AF XY: 0.00134 AC XY: 93 AN XY: 69662

African (AFR) AF: 0.000300 AC: 12 AN: 39970

American (AMR) AF: 0.0000680 AC: 1 AN: 14700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3322

East Asian (EAS) AF: 0.00 AC: 0 AN: 4584

South Asian (SAS) AF: 0.00 AC: 0 AN: 4264

European-Finnish (FIN) AF: 0.00862 AC: 81 AN: 9398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.00109 AC: 70 AN: 64334

Other (OTH) AF: 0.00 AC: 0 AN: 1972

Alfa AF: 0.00259 Hom.: 1022

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=190/10	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs55889738; hg19: chr2-73613031;