10-114830921-G-T

Position:

• chr10-114830921-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_020940.4(FHIP2A):​c.115G>T​(p.Glu39*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FHIP2A NM_020940.4 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.81

Genes affected

FHIP2A (HGNC:29320): (FHF complex subunit HOOK interacting protein 2A)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-114830921-G-T is Pathogenic according to our data. Variant chr10-114830921-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633777.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIP2A	NM_020940.4	c.115G>T	p.Glu39*	stop_gained	2/17	ENST00000369248.9	NP_065991.3
FHIP2A	NM_001135051.2	c.115G>T	p.Glu39*	stop_gained	2/17		NP_001128523.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIP2A	ENST00000369248.9	c.115G>T	p.Glu39*	stop_gained	2/17	1	NM_020940.4	ENSP00000358251.4
FHIP2A	ENST00000369250.7	c.115G>T	p.Glu39*	stop_gained	2/17	1		ENSP00000358253.3
FHIP2A	ENST00000710382.1	c.211G>T	p.Glu71*	stop_gained	2/17			ENSP00000518239.1
FHIP2A	ENST00000369246.1	c.115G>T	p.Glu39*	stop_gained	2/3	2		ENSP00000358249.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Tolun Lab, Human Genetics Laboratory, Bogazici University

May 24, 2019

Anazi et al., 2017 reported homozygous missense c.248T>C (p.(Leu83Pro)) mutation in FAM160B1, in 3 siblings with a similar clinical manifestation with our patient, who has syndromic intellectual disability. The mutation we have found is a nonsense mutation, which probably leads to nonsense mediated mRNA decay. Our patient is the only one in the family who has the homozygous mutant genotype. The mutation is not found in any databases such as 1000 Genomes or gnomAD. Therefore, although the function of the protein is not known, we evaluated our mutation to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.43
GERP RS		4.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1592013653; hg19: chr10-116590680;