Variant 6-96604769-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001322466.2(FHL5):c.179G>T(p.Arg60Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FHL5
NM_001322466.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.19

Variant links:

Genes affected

FHL5 (HGNC:17371): (four and a half LIM domains 5) The protein encoded by this gene is coordinately expressed with activator of cAMP-responsive element modulator (CREM). It is associated with CREM and confers a powerful transcriptional activation function. CREM acts as a transcription factor essential for the differentiation of spermatids into mature spermatozoa. There are multiple polyadenylation sites found in this gene. Polymorphisms in this gene may be associated with susceptibility for migraine headaches. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Apr 2016]

FHL5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL5	NM_001322466.2 linkuse as main transcript	c.179G>T	p.Arg60Leu	missense_variant	3/6	ENST00000450218.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FHL5	ENST00000450218.6 linkuse as main transcript	c.179G>T	p.Arg60Leu	missense_variant	3/6	5	NM_001322466.2	P1
FHL5	ENST00000326771.2 linkuse as main transcript	c.179G>T	p.Arg60Leu	missense_variant	4/7	1		P1
FHL5	ENST00000541107.5 linkuse as main transcript	c.179G>T	p.Arg60Leu	missense_variant	3/6	1		P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247678

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133900

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458446

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725570

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2023

The c.179G>T (p.R60L) alteration is located in exon 4 (coding exon 2) of the FHL5 gene. This alteration results from a G to T substitution at nucleotide position 179, causing the arginine (R) at amino acid position 60 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;D;T

Eigen

Benign

-0.087

Eigen_PC

Benign

0.0095

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.93

D;D;.

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.5

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-5.6

D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.016

D;D;D

Polyphen

0.081

B;.;B

Vest4

0.39

MutPred

0.67

Gain of catalytic residue at R60 (P = 0.0039);Gain of catalytic residue at R60 (P = 0.0039);Gain of catalytic residue at R60 (P = 0.0039);

MVP

0.82

MPC

0.037

ClinPred

0.97

GERP RS

2.2

Varity_R

0.27

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over