NM_001378454.1:c.11872+18G>A

Variant names:

• chr2-73600899-G-A
• rs139647347
• NM_001378454.1:c.11872+18G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378454.1(ALMS1):​c.11872+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00789 in 1,608,876 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (77 hom.)
• Consequence: ALMS1 NM_001378454.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.902
• 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-73600899-G-A is Benign according to our data. Variant chr2-73600899-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 387350.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00503 (767/152358) while in subpopulation SAS AF = 0.0127 (61/4822). AF 95% confidence interval is 0.0101. There are 3 homozygotes in GnomAd4. There are 363 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.11872+18G>A		intron	N/A	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.11872+18G>A		intron	N/A	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.11872+18G>A		intron	N/A	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.11746+18G>A		intron	N/A	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.11491+18G>A		intron	N/A	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 767 AN: 152240 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00807

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00524 AC: 1287 AN: 245654 AF XY: 0.00586

Gnomad AFR exome AF: 0.00140

Gnomad AMR exome AF: 0.000815

Gnomad ASJ exome AF: 0.00321

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000419

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00449

GnomAD4 exome AF: 0.00819 AC: 11926 AN: 1456518 Hom.: 77 Cov.: 30 AF XY: 0.00832 AC XY: 6026 AN XY: 724620

African (AFR) AF: 0.00157 AC: 52 AN: 33142

American (AMR) AF: 0.000965 AC: 43 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00368 AC: 96 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.0131 AC: 1122 AN: 85748

European-Finnish (FIN) AF: 0.00109 AC: 58 AN: 53316

Middle Eastern (MID) AF: 0.00227 AC: 13 AN: 5726

European-Non Finnish (NFE) AF: 0.00913 AC: 10123 AN: 1108348

Other (OTH) AF: 0.00697 AC: 419 AN: 60150

GnomAD4 genome AF: 0.00503 AC: 767 AN: 152358 Hom.: 3 Cov.: 32 AF XY: 0.00487 AC XY: 363 AN XY: 74514

African (AFR) AF: 0.00168 AC: 70 AN: 41594

American (AMR) AF: 0.00124 AC: 19 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4822

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00807 AC: 549 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00478 Hom.: 0

Bravo AF: 0.00491

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	2	Alstrom syndrome (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.8
DANN	Benign	0.44
PhyloP100		0.90
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: rs139647347; hg19: chr2-73828026;