6-96610683-G-A

Position:

• chr6-96610683-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001322466.2(FHL5):​c.616G>A​(p.Asp206Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FHL5 NM_001322466.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3828491).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL5	NM_001322466.2	c.616G>A	p.Asp206Asn	missense_variant	5/6	ENST00000450218.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL5	ENST00000450218.6	c.616G>A	p.Asp206Asn	missense_variant	5/6	5	NM_001322466.2	P1
FHL5	ENST00000326771.2	c.616G>A	p.Asp206Asn	missense_variant	6/7	1		P1
FHL5	ENST00000541107.5	c.616G>A	p.Asp206Asn	missense_variant	5/6	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461350 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727022

Gnomad4 AFR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.616G>A (p.D206N) alteration is located in exon 6 (coding exon 4) of the FHL5 gene. This alteration results from a G to A substitution at nucleotide position 616, causing the aspartic acid (D) at amino acid position 206 to be replaced by an asparagine (N). 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	0.072
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;D;T
Eigen	Benign	0.036
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;.
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.90	L;.;L
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.6	D;N;D
REVEL	Uncertain	0.32
Sift	Benign	0.094	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.10	B;.;B
Vest4		0.18
MutPred		0.56		Loss of solvent accessibility (P = 0.1279);Loss of solvent accessibility (P = 0.1279);Loss of solvent accessibility (P = 0.1279);
MVP		0.67
MPC		0.16
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.20
gMVP		0.51

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: rs754828656; hg19: chr6-97058559; COSMIC: COSV58740066;