2-73385903-TGGAGGAGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr2-73385903-T-TGGAGGAGGAGGAGGAGGAGGA
• rs55889738
• NM_001378454.1:c.54_74dupGGAGGAGGAGGAGGAGGAGGA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_001378454.1(ALMS1):​c.54_74dupGGAGGAGGAGGAGGAGGAGGA​(p.Glu19_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. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E25E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000084 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• 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, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen

ENSG00000285068 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-T-TGGAGGAGGAGGAGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGAGGAGGAGGAGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.54_74dupGGAGGAGGAGGAGGAGGAGGA	p.Glu19_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.54_74dupGGAGGAGGAGGAGGAGGAGGA	p.Glu19_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.54_74dupGGAGGAGGAGGAGGAGGAGGA	p.Glu19_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.54_74dupGGAGGAGGAGGAGGAGGAGGA	p.Glu19_Glu25dup	disruptive_inframe_insertion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.54_74dupGGAGGAGGAGGAGGAGGAGGA	p.Glu19_Glu25dup	disruptive_inframe_insertion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.0000836 AC: 12 AN: 143532 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000870

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000622

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000735 AC: 41 AN: 557726 Hom.: 0 Cov.: 0 AF XY: 0.0000638 AC XY: 19 AN XY: 297820

⚠️ 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: 0.0000567 AC: 1 AN: 17646

East Asian (EAS) AF: 0.000294 AC: 9 AN: 30664

South Asian (SAS) AF: 0.0000358 AC: 2 AN: 55942

European-Finnish (FIN) AF: 0.000110 AC: 4 AN: 36320

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

European-Non Finnish (NFE) AF: 0.0000711 AC: 24 AN: 337580

Other (OTH) AF: 0.0000332 AC: 1 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: 0.0000835 AC: 12 AN: 143636 Hom.: 0 Cov.: 0 AF XY: 0.0000718 AC XY: 5 AN XY: 69662

African (AFR) AF: 0.0000250 AC: 1 AN: 39970

American (AMR) AF: 0.0000680 AC: 1 AN: 14700

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

East Asian (EAS) AF: 0.000873 AC: 4 AN: 4584

South Asian (SAS) AF: 0.00 AC: 0 AN: 4264

European-Finnish (FIN) AF: 0.000213 AC: 2 AN: 9398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000622 AC: 4 AN: 64334

Other (OTH) AF: 0.00 AC: 0 AN: 1972

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs55889738;

hg19: chr2-73613031;