1-201194249-C-A

Variant names:

• chr1-201194249-C-A
• rs1405374899
• NM_001164586.2:c.103C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001164586.2(IGFN1):​c.103C>A​(p.Pro35Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P35A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGFN1 NM_001164586.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• Publications: 0 publications found

Genes affected

IGFN1 (HGNC:24607): (immunoglobulin like and fibronectin type III domain containing 1) Predicted to be involved in homophilic cell adhesion via plasma membrane adhesion molecules; retina layer formation; and synapse assembly. Predicted to be located in Z disc and nucleus. Predicted to be active in synapse. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164586.2. 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
	IGFN1	NM_001164586.2	MANE Select	c.103C>A	p.Pro35Thr	missense	Exon 3 of 24	NP_001158058.1	Q86VF2-5
	IGFN1	NM_001367841.1		c.103C>A	p.Pro35Thr	missense	Exon 3 of 25	NP_001354770.1	Q86VF2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFN1	ENST00000335211.9	TSL:5 MANE Select	c.103C>A	p.Pro35Thr	missense	Exon 3 of 24	ENSP00000334714.4	Q86VF2-5
	IGFN1	ENST00000437879.6	TSL:1	n.103C>A		non_coding_transcript_exon	Exon 3 of 26	ENSP00000399041.2	Q86VF2-4
	IGFN1	ENST00000295591.12	TSL:5	c.103C>A	p.Pro35Thr	missense	Exon 3 of 25	ENSP00000295591.9	Q86VF2-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.8
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.48
MutPred		0.79		Gain of phosphorylation at P35 (P = 0.0809)
MVP		0.60
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.29
gMVP		0.39
Mutation Taster		=219/81	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: rs1405374899; hg19: chr1-201163377;