2-73385903-TGGAGGA-T

Variant names:

• chr2-73385903-TGGAGGA-T
• rs55889738
• NM_001378454.1:c.69_74delGGAGGA

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.69_74delGGAGGA​(p.Glu24_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 0.294 in 700,128 control chromosomes in the GnomAD database, including 21,830 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E23E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (12811 hom., cov: 0)
  • Exomes 𝑓: 0.27 (9019 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.21
• 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-TGGAGGA-T is Benign according to our data. Variant chr2-73385903-TGGAGGA-T is described in ClinVar as Benign. ClinVar VariationId is 221075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.642 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.69_74delGGAGGA	p.Glu24_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.69_74delGGAGGA	p.Glu24_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.69_74delGGAGGA	p.Glu24_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.69_74delGGAGGA	p.Glu24_Glu25del	disruptive_inframe_deletion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.69_74delGGAGGA	p.Glu24_Glu25del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.394 AC: 56506 AN: 143428 Hom.: 12779 Cov.: 0

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.254

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.354

GnomAD2 exomes AF: 0.286 AC: 23877 AN: 83366 AF XY: 0.281

Gnomad AFR exome AF: 0.613

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.194

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.300

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.268 AC: 148993 AN: 556596 Hom.: 9019 AF XY: 0.265 AC XY: 78880 AN XY: 297226

African (AFR) AF: 0.514 AC: 8079 AN: 15706

American (AMR) AF: 0.246 AC: 7557 AN: 30756

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 4105 AN: 17630

East Asian (EAS) AF: 0.213 AC: 6516 AN: 30630

South Asian (SAS) AF: 0.245 AC: 13691 AN: 55906

European-Finnish (FIN) AF: 0.245 AC: 8884 AN: 36252

Middle Eastern (MID) AF: 0.250 AC: 605 AN: 2418

European-Non Finnish (NFE) AF: 0.271 AC: 91429 AN: 337232

Other (OTH) AF: 0.270 AC: 8127 AN: 30066

GnomAD4 genome AF: 0.394 AC: 56594 AN: 143532 Hom.: 12811 Cov.: 0 AF XY: 0.389 AC XY: 27093 AN XY: 69610

African (AFR) AF: 0.648 AC: 25889 AN: 39930

American (AMR) AF: 0.308 AC: 4526 AN: 14678

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 905 AN: 3322

East Asian (EAS) AF: 0.204 AC: 937 AN: 4584

South Asian (SAS) AF: 0.284 AC: 1210 AN: 4258

European-Finnish (FIN) AF: 0.272 AC: 2551 AN: 9392

Middle Eastern (MID) AF: 0.257 AC: 69 AN: 268

European-Non Finnish (NFE) AF: 0.304 AC: 19552 AN: 64298

Other (OTH) AF: 0.353 AC: 697 AN: 1972

Alfa AF: 0.237 Hom.: 1022

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=197/3	polymorphism (auto)

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: COSV52501924; COSMIC: COSV52501924;