chr2-73385903-T-TGGAGGA

Variant names:

• chr2-73385903-T-TGGAGGA
• rs55889738
• NM_001378454.1:c.69_74dupGGAGGA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BA1

The NM_001378454.1(ALMS1):​c.69_74dupGGAGGA​(p.Glu24_Glu25dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E25E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.059 (291 hom., cov: 0)
  • Exomes 𝑓: 0.063 (154 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:12
• Conservation: PhyloP100: 0.369
• 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-T-TGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218713.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 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_74dupGGAGGA	p.Glu24_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.69_74dupGGAGGA	p.Glu24_Glu25dup	disruptive_inframe_insertion	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_74dupGGAGGA	p.Glu24_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.69_74dupGGAGGA	p.Glu24_Glu25dup	disruptive_inframe_insertion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.69_74dupGGAGGA	p.Glu24_Glu25dup	disruptive_inframe_insertion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 8536 AN: 143400 Hom.: 292 Cov.: 0

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0698

Gnomad EAS AF: 0.0755

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0617

Gnomad MID AF: 0.0603

Gnomad NFE AF: 0.0672

Gnomad OTH AF: 0.0595

GnomAD2 exomes AF: 0.0668 AC: 5566 AN: 83366 AF XY: 0.0657

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0393

Gnomad EAS exome AF: 0.0629

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0477

GnomAD4 exome AF: 0.0632 AC: 35210 AN: 557130 Hom.: 154 Cov.: 0 AF XY: 0.0645 AC XY: 19197 AN XY: 297462

African (AFR) AF: 0.0218 AC: 345 AN: 15792

American (AMR) AF: 0.106 AC: 3314 AN: 31164

Ashkenazi Jewish (ASJ) AF: 0.0554 AC: 977 AN: 17620

East Asian (EAS) AF: 0.0749 AC: 2295 AN: 30636

South Asian (SAS) AF: 0.0967 AC: 5400 AN: 55846

European-Finnish (FIN) AF: 0.0494 AC: 1792 AN: 36292

Middle Eastern (MID) AF: 0.0665 AC: 161 AN: 2422

European-Non Finnish (NFE) AF: 0.0566 AC: 19101 AN: 337270

Other (OTH) AF: 0.0607 AC: 1825 AN: 30088

GnomAD4 genome AF: 0.0594 AC: 8530 AN: 143504 Hom.: 291 Cov.: 0 AF XY: 0.0622 AC XY: 4327 AN XY: 69588

African (AFR) AF: 0.0227 AC: 908 AN: 39946

American (AMR) AF: 0.105 AC: 1537 AN: 14686

Ashkenazi Jewish (ASJ) AF: 0.0698 AC: 232 AN: 3322

East Asian (EAS) AF: 0.0753 AC: 345 AN: 4580

South Asian (SAS) AF: 0.112 AC: 475 AN: 4256

European-Finnish (FIN) AF: 0.0617 AC: 579 AN: 9386

Middle Eastern (MID) AF: 0.0602 AC: 16 AN: 266

European-Non Finnish (NFE) AF: 0.0672 AC: 4322 AN: 64268

Other (OTH) AF: 0.0589 AC: 116 AN: 1968

Alfa AF: 0.0447 Hom.: 1022

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	2	Alstrom syndrome (7)
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.37
Mutation Taster		=78/22	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: COSV105092294; COSMIC: COSV105092294;