NM_001378454.1:c.2764C>T

Variant names:

• chr2-73449291-C-T
• rs143885319
• NM_001378454.1:c.2764C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378454.1(ALMS1):​c.2764C>T​(p.Leu922Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000792 in 1,613,850 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (4 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.155
• 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: Unknown, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P, Orphanet

ENSG00000295621 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-73449291-C-T is Benign according to our data. Variant chr2-73449291-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00437 (664/152066) while in subpopulation AFR AF = 0.0153 (635/41486). AF 95% confidence interval is 0.0143. There are 2 homozygotes in GnomAd4. There are 314 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.2764C>T	p.Leu922Leu	synonymous	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.2764C>T	p.Leu922Leu	synonymous	Exon 8 of 23	NP_055935.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.2764C>T	p.Leu922Leu	synonymous	Exon 8 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.2638C>T	p.Leu880Leu	synonymous	Exon 7 of 22	ENSP00000478155.1
	ALMS1	ENST00000684548.1		c.2383C>T	p.Leu795Leu	synonymous	Exon 6 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 661 AN: 151950 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00117 AC: 291 AN: 248230 AF XY: 0.000957

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000420 AC: 614 AN: 1461784 Hom.: 4 Cov.: 40 AF XY: 0.000353 AC XY: 257 AN XY: 727196

African (AFR) AF: 0.0143 AC: 480 AN: 33472

American (AMR) AF: 0.000828 AC: 37 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111966

Other (OTH) AF: 0.00103 AC: 62 AN: 60392

GnomAD4 genome AF: 0.00437 AC: 664 AN: 152066 Hom.: 2 Cov.: 33 AF XY: 0.00422 AC XY: 314 AN XY: 74332

African (AFR) AF: 0.0153 AC: 635 AN: 41486

American (AMR) AF: 0.00137 AC: 21 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67966

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00205 Hom.: 1

Bravo AF: 0.00465

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.16
DANN	Benign	0.42
PhyloP100		-0.15
PromoterAI		0.0044	Neutral
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: rs143885319; hg19: chr2-73676418;