2-73385903-T-TGGAGGAGGAGGAGGA

Variant names:

• chr2-73385903-T-TGGAGGAGGAGGAGGA
• rs55889738
• NM_001378454.1:c.60_74dupGGAGGAGGAGGAGGA

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS1

The NM_001378454.1(ALMS1):​c.60_74dupGGAGGAGGAGGAGGA​(p.Glu21_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 0.00042 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-T-TGGAGGAGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGAGGAGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000425 (61/143628) while in subpopulation EAS AF = 0.00656 (30/4576). AF 95% confidence interval is 0.00472. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.60_74dupGGAGGAGGAGGAGGA	p.Glu21_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.60_74dupGGAGGAGGAGGAGGA	p.Glu21_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.60_74dupGGAGGAGGAGGAGGA	p.Glu21_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.60_74dupGGAGGAGGAGGAGGA	p.Glu21_Glu25dup	disruptive_inframe_insertion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.60_74dupGGAGGAGGAGGAGGA	p.Glu21_Glu25dup	disruptive_inframe_insertion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.000432 AC: 62 AN: 143524 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000613

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00675

Gnomad SAS AF: 0.000468

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000155

Gnomad OTH AF: 0.00102

GnomAD4 exome AF: 0.000368 AC: 205 AN: 557722 Hom.: 0 Cov.: 0 AF XY: 0.000336 AC XY: 100 AN XY: 297818

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

African (AFR) AF: 0.000127 AC: 2 AN: 15796

American (AMR) AF: 0.000192 AC: 6 AN: 31236

Ashkenazi Jewish (ASJ) AF: 0.000113 AC: 2 AN: 17646

East Asian (EAS) AF: 0.00323 AC: 99 AN: 30664

South Asian (SAS) AF: 0.000125 AC: 7 AN: 55944

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

Middle Eastern (MID) AF: 0.000413 AC: 1 AN: 2422

European-Non Finnish (NFE) AF: 0.000187 AC: 63 AN: 337574

Other (OTH) AF: 0.000697 AC: 21 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: 0.000425 AC: 61 AN: 143628 Hom.: 0 Cov.: 0 AF XY: 0.000502 AC XY: 35 AN XY: 69660

African (AFR) AF: 0.000175 AC: 7 AN: 39970

American (AMR) AF: 0.000612 AC: 9 AN: 14700

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

East Asian (EAS) AF: 0.00656 AC: 30 AN: 4576

South Asian (SAS) AF: 0.000469 AC: 2 AN: 4264

European-Finnish (FIN) AF: 0.000106 AC: 1 AN: 9398

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

European-Non Finnish (NFE) AF: 0.000155 AC: 10 AN: 64334

Other (OTH) AF: 0.00101 AC: 2 AN: 1972

Alfa AF: 0.00 Hom.: 1022

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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;