ENST00000484298:c.-78A>G

Variant names:

• chr2-73385791-A-G
• rs571728800
• ENST00000484298.5:c.-78A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The ENST00000484298.5(ALMS1):​c.-78A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 629,364 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00069 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: ALMS1 ENST00000484298.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000686 (104/151698) while in subpopulation SAS AF = 0.00752 (36/4790). AF 95% confidence interval is 0.00558. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000484298.5. 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_015120.4		c.-78A>G		5_prime_UTR	Exon 1 of 23	NP_055935.4	Q8TCU4
	ALMS1	NM_001378454.1	MANE Select	c.-78A>G		upstream_gene	N/A	NP_001365383.1	Q8TCU4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000484298.5	TSL:1	c.-78A>G		5_prime_UTR	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.-78A>G		upstream_gene	N/A	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000614410.4	TSL:5	c.-78A>G		upstream_gene	N/A	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes AF: 0.000693 AC: 105 AN: 151586 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00390

Gnomad SAS AF: 0.00772

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000369

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.00121 AC: 579 AN: 477666 Hom.: 6 Cov.: 4 AF XY: 0.00166 AC XY: 427 AN XY: 256496

African (AFR) AF: 0.0000842 AC: 1 AN: 11878

American (AMR) AF: 0.00 AC: 0 AN: 23690

Ashkenazi Jewish (ASJ) AF: 0.0000652 AC: 1 AN: 15346

East Asian (EAS) AF: 0.00165 AC: 48 AN: 29132

South Asian (SAS) AF: 0.00789 AC: 394 AN: 49946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31294

Middle Eastern (MID) AF: 0.00425 AC: 9 AN: 2116

European-Non Finnish (NFE) AF: 0.000352 AC: 101 AN: 286898

Other (OTH) AF: 0.000914 AC: 25 AN: 27366

GnomAD4 genome AF: 0.000686 AC: 104 AN: 151698 Hom.: 1 Cov.: 32 AF XY: 0.000715 AC XY: 53 AN XY: 74154

African (AFR) AF: 0.000387 AC: 16 AN: 41382

American (AMR) AF: 0.000262 AC: 4 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00391 AC: 20 AN: 5118

South Asian (SAS) AF: 0.00752 AC: 36 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000369 AC: 25 AN: 67828

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.0000530 Hom.: 0

Bravo AF: 0.000540

Asia WGS AF: 0.00116 AC: 4 AN: 3462

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Alstrom syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.67
PhyloP100		3.2
PromoterAI		0.051	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs571728800; hg19: chr2-73612919;