17-2691781-C-T

Variant names:

• chr17-2691781-C-T
• rs766167419
• NM_001366661.1:c.3769G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001366661.1(CLUH):​c.3769G>A​(p.Ala1257Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,440,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1257S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLUH NM_001366661.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

Genes affected

CLUH (HGNC:29094): (clustered mitochondria homolog) Enables mRNA binding activity. Involved in intracellular distribution of mitochondria. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32313874).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366661.1. 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
	CLUH	NM_001366661.1	MANE Select	c.3769G>A	p.Ala1257Thr	missense	Exon 24 of 26	NP_001353590.1	A0A494C0R8
	CLUH	NM_015229.4		c.3766G>A	p.Ala1256Thr	missense	Exon 24 of 26	NP_056044.4
	CLUH	NM_001366662.1		c.3652G>A	p.Ala1218Thr	missense	Exon 24 of 26	NP_001353591.1	O75153

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLUH	ENST00000651024.2	MANE Select	c.3769G>A	p.Ala1257Thr	missense	Exon 24 of 26	ENSP00000498679.1	A0A494C0R8
	CLUH	ENST00000574210.5	TSL:1	n.1093G>A		non_coding_transcript_exon	Exon 8 of 9
	CLUH	ENST00000876318.1		c.3787G>A	p.Ala1263Thr	missense	Exon 24 of 26	ENSP00000546377.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440344 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714688

African (AFR) AF: 0.00 AC: 0 AN: 33058

American (AMR) AF: 0.00 AC: 0 AN: 41392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25652

East Asian (EAS) AF: 0.00 AC: 0 AN: 38616

South Asian (SAS) AF: 0.00 AC: 0 AN: 83394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102266

Other (OTH) AF: 0.0000168 AC: 1 AN: 59550

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.29	N
REVEL	Uncertain	0.32
Sift	Benign	0.47	T
Sift4G	Benign	1.0	T
Polyphen		0.060	B
Vest4		0.78
MutPred		0.61		Gain of catalytic residue at A1218 (P = 0.0582)
MVP		0.66
MPC		0.32
ClinPred		0.50	D
GERP RS		3.6
Varity_R		0.056
gMVP		0.63
Mutation Taster		=71/29	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: rs766167419; hg19: chr17-2595075;