NM_001378454.1:c.10214-741A>G

Variant names:

• chr2-73558231-A-G
• rs6546847
• NM_001378454.1:c.10214-741A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378454.1(ALMS1):​c.10214-741A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 152,106 control chromosomes in the GnomAD database, including 15,948 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (15948 hom., cov: 32)
• Consequence: ALMS1 NM_001378454.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 23 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 Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.10214-741A>G		intron_variant	Intron 14 of 22	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.10214-741A>G		intron_variant	Intron 14 of 22		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.10214-741A>G		intron_variant	Intron 14 of 22	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58855 AN: 151988 Hom.: 15889 Cov.: 32

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.00712

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.338

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.388 AC: 58976 AN: 152106 Hom.: 15948 Cov.: 32 AF XY: 0.381 AC XY: 28298 AN XY: 74346

African (AFR) AF: 0.769 AC: 31874 AN: 41464

American (AMR) AF: 0.374 AC: 5716 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 659 AN: 3470

East Asian (EAS) AF: 0.00713 AC: 37 AN: 5186

South Asian (SAS) AF: 0.151 AC: 726 AN: 4822

European-Finnish (FIN) AF: 0.242 AC: 2564 AN: 10590

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16367 AN: 67966

Other (OTH) AF: 0.334 AC: 706 AN: 2112

Alfa AF: 0.283 Hom.: 21840

Bravo AF: 0.416

Asia WGS AF: 0.122 AC: 426 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.6
DANN	Benign	0.68
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs6546847; hg19: chr2-73785358;