rs200459890

Variant names:

• chr2-73450871-A-G
• rs200459890
• NM_001378454.1:c.4344A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001378454.1(ALMS1):​c.4344A>G​(p.Leu1448Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000958 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1448L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (1 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.240
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-73450871-A-G is Benign according to our data. Variant chr2-73450871-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 392005.
• BP7: Synonymous conserved (PhyloP=0.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000768 (117/152308) while in subpopulation AMR AF = 0.00347 (53/15292). AF 95% confidence interval is 0.00272. There are 0 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.4344A>G	p.Leu1448Leu	synonymous	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.4344A>G	p.Leu1448Leu	synonymous	Exon 8 of 23	NP_055935.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.4344A>G	p.Leu1448Leu	synonymous	Exon 8 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.4218A>G	p.Leu1406Leu	synonymous	Exon 7 of 22	ENSP00000478155.1
	ALMS1	ENST00000684548.1		c.3963A>G	p.Leu1321Leu	synonymous	Exon 6 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000682 AC: 170 AN: 249282 AF XY: 0.000658

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000699

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000978 AC: 1430 AN: 1461822 Hom.: 1 Cov.: 39 AF XY: 0.000919 AC XY: 668 AN XY: 727212

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00203 AC: 91 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86254

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00114 AC: 1270 AN: 1111980

Other (OTH) AF: 0.000695 AC: 42 AN: 60392

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74486

African (AFR) AF: 0.000217 AC: 9 AN: 41558

American (AMR) AF: 0.00347 AC: 53 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000594 Hom.: 0

Bravo AF: 0.000914

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Alstrom syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.65
DANN	Benign	0.37
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs200459890; hg19: chr2-73677998; COSMIC: COSV52511574; COSMIC: COSV52511574;