rs199649563

Variant names:

• chr2-73450731-A-G
• rs199649563
• NM_001378454.1:c.4204A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001378454.1(ALMS1):​c.4204A>G​(p.Thr1402Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,612,388 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1402N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (1 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: -2.05
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013007224).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000992 (145/1461454) while in subpopulation MID AF = 0.00243 (14/5766). AF 95% confidence interval is 0.00147. There are 1 homozygotes in GnomAdExome4. There are 83 alleles in the male GnomAdExome4 subpopulation. Median coverage is 42. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.4204A>G	p.Thr1402Ala	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.4204A>G	p.Thr1402Ala	missense	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.4204A>G	p.Thr1402Ala	missense	Exon 8 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.4078A>G	p.Thr1360Ala	missense	Exon 7 of 22	ENSP00000478155.1
	ALMS1	ENST00000684548.1		c.3823A>G	p.Thr1275Ala	missense	Exon 6 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes AF: 0.000166 AC: 25 AN: 150816 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000597

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000838

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000483

GnomAD2 exomes AF: 0.000209 AC: 52 AN: 249340 AF XY: 0.000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000992 AC: 145 AN: 1461454 Hom.: 1 Cov.: 42 AF XY: 0.000114 AC XY: 83 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.000313 AC: 14 AN: 44704

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

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

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111668

Other (OTH) AF: 0.000166 AC: 10 AN: 60378

GnomAD4 genome AF: 0.000159 AC: 24 AN: 150934 Hom.: 1 Cov.: 32 AF XY: 0.000190 AC XY: 14 AN XY: 73700

African (AFR) AF: 0.0000244 AC: 1 AN: 40990

American (AMR) AF: 0.000596 AC: 9 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.000839 AC: 4 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10388

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67796

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000152 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000199 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Alstrom syndrome (3)
-	2	-	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.0010
DANN	Benign	0.38
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.0
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.22	T
Vest4		0.044
MVP		0.085
ClinPred		0.017	T
GERP RS		-7.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.033
Mutation Taster		=86/14	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: rs199649563; hg19: chr2-73677858;