rs10199680

Positions:

• chr2-73534815-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):​c.9782-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00639 in 1,612,400 control chromosomes in the GnomAD database, including 556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (292 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (264 hom.)
• Consequence: ALMS1 NM_001378454.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.183

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-73534815-C-T is Benign according to our data. Variant chr2-73534815-C-T is described in ClinVar as [Benign]. Clinvar id is 387349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.9782-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.9782-9C>T		splice_polypyrimidine_tract_variant, intron_variant			NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.9782-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001378454.1	ENSP00000482968	P3

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5110 AN: 152034 Hom.: 287 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0259

GnomAD3 exomes AF: 0.00869 AC: 2165 AN: 249192 Hom.: 126 AF XY: 0.00621 AC XY: 840 AN XY: 135208

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.00519

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000531

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00353 AC: 5152 AN: 1460248 Hom.: 264 Cov.: 31 AF XY: 0.00303 AC XY: 2201 AN XY: 726562

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.00611

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000319

Gnomad4 OTH exome AF: 0.00740

GnomAD4 genome AF: 0.0338 AC: 5144 AN: 152152 Hom.: 292 Cov.: 33 AF XY: 0.0329 AC XY: 2447 AN XY: 74382

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0164 Hom.: 91

Bravo AF: 0.0385

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.9779-9C>T in intron 11 of ALMS1: This variant is not expected to have clinical significance because a C>T change at this position does not diverge from the sp lice consensus sequence and is therefore unlikely to impact splicing. It has bee n identified in 12.00% (1176/9796) of African chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs10199680). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -

Alstrom syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs10199680; hg19: chr2-73761942;