chr2-73385903-TGGAGGAGGA-T

Variant names:

• chr2-73385903-TGGAGGAGGA-T
• rs55889738
• NM_001378454.1:c.66_74delGGAGGAGGA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001378454.1(ALMS1):​c.66_74delGGAGGAGGA​(p.Glu23_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 0.0129 in 672,168 control chromosomes in the GnomAD database, including 48 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E22E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., cov: 0)
  • Exomes 𝑓: 0.015 (38 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-TGGAGGAGGA-T is Benign according to our data. Variant chr2-73385903-TGGAGGAGGA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00658 (944/143536) while in subpopulation NFE AF = 0.0114 (731/64316). AF 95% confidence interval is 0.0107. There are 10 homozygotes in GnomAd4. There are 415 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.66_74delGGAGGAGGA	p.Glu23_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.66_74delGGAGGAGGA	p.Glu23_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.66_74delGGAGGAGGA	p.Glu23_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.66_74delGGAGGAGGA	p.Glu23_Glu25del	disruptive_inframe_deletion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.66_74delGGAGGAGGA	p.Glu23_Glu25del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 944 AN: 143440 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00363

Gnomad AMR AF: 0.00300

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00413

Gnomad SAS AF: 0.00609

Gnomad FIN AF: 0.000641

Gnomad MID AF: 0.00355

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00768

GnomAD2 exomes AF: 0.0196 AC: 1632 AN: 83366 AF XY: 0.0202

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00969

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.0108

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0146 AC: 7739 AN: 528632 Hom.: 38 AF XY: 0.0145 AC XY: 4082 AN XY: 282412

African (AFR) AF: 0.0318 AC: 409 AN: 12862

American (AMR) AF: 0.00953 AC: 287 AN: 30126

Ashkenazi Jewish (ASJ) AF: 0.00500 AC: 85 AN: 17004

East Asian (EAS) AF: 0.00472 AC: 139 AN: 29472

South Asian (SAS) AF: 0.0144 AC: 766 AN: 53104

European-Finnish (FIN) AF: 0.00540 AC: 188 AN: 34834

Middle Eastern (MID) AF: 0.00694 AC: 16 AN: 2304

European-Non Finnish (NFE) AF: 0.0170 AC: 5447 AN: 320622

Other (OTH) AF: 0.0142 AC: 402 AN: 28304

GnomAD4 genome AF: 0.00658 AC: 944 AN: 143536 Hom.: 10 Cov.: 0 AF XY: 0.00596 AC XY: 415 AN XY: 69596

African (AFR) AF: 0.00248 AC: 99 AN: 39936

American (AMR) AF: 0.00299 AC: 44 AN: 14694

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

East Asian (EAS) AF: 0.00414 AC: 19 AN: 4584

South Asian (SAS) AF: 0.00610 AC: 26 AN: 4264

European-Finnish (FIN) AF: 0.000641 AC: 6 AN: 9356

Middle Eastern (MID) AF: 0.00376 AC: 1 AN: 266

European-Non Finnish (NFE) AF: 0.0114 AC: 731 AN: 64316

Other (OTH) AF: 0.00761 AC: 15 AN: 1972

Alfa AF: 0.0140 Hom.: 1022

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Alstrom syndrome (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=198/2	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; COSMIC: COSV106054170; COSMIC: COSV106054170;