6-96604769-G-T

Variant names:

• chr6-96604769-G-T
• rs770381788
• NM_001322466.2:c.179G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322466.2. 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
	FHL5	NM_001322466.2	MANE Select	c.179G>T	p.Arg60Leu	missense	Exon 3 of 6	NP_001309395.1	Q5TD97
	FHL5	NM_001170807.3		c.179G>T	p.Arg60Leu	missense	Exon 3 of 6	NP_001164278.1	Q5TD97
	FHL5	NM_001322467.1		c.179G>T	p.Arg60Leu	missense	Exon 4 of 7	NP_001309396.1	Q5TD97

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL5	ENST00000450218.6	TSL:5 MANE Select	c.179G>T	p.Arg60Leu	missense	Exon 3 of 6	ENSP00000396390.2	Q5TD97
	FHL5	ENST00000326771.2	TSL:1	c.179G>T	p.Arg60Leu	missense	Exon 4 of 7	ENSP00000326022.2	Q5TD97
	FHL5	ENST00000541107.5	TSL:1	c.179G>T	p.Arg60Leu	missense	Exon 3 of 6	ENSP00000442357.1	Q5TD97

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247678 AF XY: 0.00000747

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458446 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725570

African (AFR) AF: 0.0000300 AC: 1 AN: 33278

American (AMR) AF: 0.00 AC: 0 AN: 43932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110704

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.0095
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.2
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.016	D
Polyphen		0.081	B
Vest4		0.39
MutPred		0.67		Gain of catalytic residue at R60 (P = 0.0039)
MVP		0.82
MPC		0.037
ClinPred		0.97	D
GERP RS		2.2
Varity_R		0.27
gMVP		0.57
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs770381788; hg19: chr6-97052645;