2-73385903-TGGAGGAGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr2-73385903-T-TGGAGGAGGAGGAGGAGGAGGAGGAGGA
• rs55889738
• NM_001378454.1:c.48_74dupGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001378454.1(ALMS1):​c.48_74dupGGAGGAGGAGGAGGAGGAGGAGGAGGA​(p.Glu17_Glu25dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E25E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000070 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1

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.48_74dupGGAGGAGGAGGAGGAGGAGGAGGAGGA	p.Glu17_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.48_74dupGGAGGAGGAGGAGGAGGAGGAGGAGGA	p.Glu17_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.48_74dupGGAGGAGGAGGAGGAGGAGGAGGAGGA	p.Glu17_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.48_74dupGGAGGAGGAGGAGGAGGAGGAGGAGGA	p.Glu17_Glu25dup	disruptive_inframe_insertion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.48_74dupGGAGGAGGAGGAGGAGGAGGAGGAGGA	p.Glu17_Glu25dup	disruptive_inframe_insertion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.00000697 AC: 1 AN: 143532 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000215 AC: 12 AN: 557742 Hom.: 0 Cov.: 0 AF XY: 0.0000201 AC XY: 6 AN XY: 297828

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

African (AFR) AF: 0.00 AC: 0 AN: 15796

American (AMR) AF: 0.00 AC: 0 AN: 31236

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

East Asian (EAS) AF: 0.0000652 AC: 2 AN: 30670

South Asian (SAS) AF: 0.0000357 AC: 2 AN: 55946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36320

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

European-Non Finnish (NFE) AF: 0.0000207 AC: 7 AN: 337586

Other (OTH) AF: 0.0000332 AC: 1 AN: 30120

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000693889), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000697 AC: 1 AN: 143532 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 69544

African (AFR) AF: 0.00 AC: 0 AN: 39854

American (AMR) AF: 0.00 AC: 0 AN: 14682

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4598

South Asian (SAS) AF: 0.000234 AC: 1 AN: 4270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64346

Other (OTH) AF: 0.00 AC: 0 AN: 1954

ClinVar

Not reported in ClinVar

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;