2-73534864-C-T

Variant names:

• chr2-73534864-C-T
• rs201446579
• NM_001378454.1:c.9822C>T
• ALMS1 p.Thr3274Thr

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001378454.1(ALMS1):​c.9822C>T​(p.Thr3274Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T3274T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70
• 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-73534864-C-T is Benign according to our data. Variant chr2-73534864-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1095982.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.

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.9822C>T	p.Thr3274Thr	synonymous	Exon 12 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.9822C>T	p.Thr3274Thr	synonymous	Exon 12 of 23	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.9822C>T	p.Thr3274Thr	synonymous	Exon 12 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.9696C>T	p.Thr3232Thr	synonymous	Exon 11 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000423048.5	TSL:1	n.*241C>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461316 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726970

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111616

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Alstrom syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.28
DANN	Benign	0.45
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201446579;

hg19: chr2-73761991;