6-96615649-G-C

Position:

• chr6-96615649-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001322466.2(FHL5):​c.732G>C​(p.Gln244His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: FHL5 NM_001322466.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.38

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21998912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL5	NM_001322466.2	c.732G>C	p.Gln244His	missense_variant	6/6	ENST00000450218.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL5	ENST00000450218.6	c.732G>C	p.Gln244His	missense_variant	6/6	5	NM_001322466.2	P1
FHL5	ENST00000326771.2	c.732G>C	p.Gln244His	missense_variant	7/7	1		P1
FHL5	ENST00000541107.5	c.732G>C	p.Gln244His	missense_variant	6/6	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.090	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.067
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.77	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.4	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.71	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.019	B;B
Vest4		0.39
MutPred		0.52		Loss of stability (P = 0.1345);Loss of stability (P = 0.1345);
MVP		0.71
MPC		0.055
ClinPred		0.47	T
GERP RS		4.8
Varity_R		0.20
gMVP		0.67

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: rs1771501846; hg19: chr6-97063525;