chr2-73385903-T-TGGAGGAGGA

Variant names:

• chr2-73385903-T-TGGAGGAGGA
• rs55889738
• NM_001378454.1:c.66_74dupGGAGGAGGA

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.66_74dupGGAGGAGGA​(p.Glu23_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 0.0025 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0039 (1 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 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-TGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193379.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00255 (366/143614) while in subpopulation SAS AF = 0.0136 (58/4258). AF 95% confidence interval is 0.0108. There are 2 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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_74dupGGAGGAGGA	p.Glu23_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.66_74dupGGAGGAGGA	p.Glu23_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.66_74dupGGAGGAGGA	p.Glu23_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.66_74dupGGAGGAGGA	p.Glu23_Glu25dup	disruptive_inframe_insertion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.66_74dupGGAGGAGGA	p.Glu23_Glu25dup	disruptive_inframe_insertion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 366 AN: 143510 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.000778

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00450

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00718

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.00128

Gnomad MID AF: 0.00355

Gnomad NFE AF: 0.00239

Gnomad OTH AF: 0.00307

GnomAD2 exomes AF: 0.00428 AC: 357 AN: 83366 AF XY: 0.00456

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.00683

Gnomad ASJ exome AF: 0.000937

Gnomad EAS exome AF: 0.00666

Gnomad FIN exome AF: 0.000717

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00325

GnomAD4 exome AF: 0.00389 AC: 2169 AN: 557620 Hom.: 1 Cov.: 0 AF XY: 0.00433 AC XY: 1288 AN XY: 297754

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000570 AC: 9 AN: 15796

American (AMR) AF: 0.00637 AC: 199 AN: 31224

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 25 AN: 17646

East Asian (EAS) AF: 0.0142 AC: 434 AN: 30624

South Asian (SAS) AF: 0.0117 AC: 654 AN: 55908

European-Finnish (FIN) AF: 0.00116 AC: 42 AN: 36320

Middle Eastern (MID) AF: 0.00372 AC: 9 AN: 2422

European-Non Finnish (NFE) AF: 0.00210 AC: 710 AN: 337560

Other (OTH) AF: 0.00289 AC: 87 AN: 30120

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00255 AC: 366 AN: 143614 Hom.: 2 Cov.: 0 AF XY: 0.00261 AC XY: 182 AN XY: 69648

African (AFR) AF: 0.000776 AC: 31 AN: 39968

American (AMR) AF: 0.00456 AC: 67 AN: 14696

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 5 AN: 3322

East Asian (EAS) AF: 0.00720 AC: 33 AN: 4582

South Asian (SAS) AF: 0.0136 AC: 58 AN: 4258

European-Finnish (FIN) AF: 0.00128 AC: 12 AN: 9398

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

European-Non Finnish (NFE) AF: 0.00238 AC: 153 AN: 64326

Other (OTH) AF: 0.00304 AC: 6 AN: 1972

Alfa AF: 0.00 Hom.: 1022

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	3	Alstrom syndrome (4)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

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