6-96604913-C-A

Variant names:

• chr6-96604913-C-A
• rs540080032
• NM_001322466.2:c.323C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001322466.2(FHL5):​c.323C>A​(p.Thr108Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000056 in 1,606,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FHL5 NM_001322466.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36640066).

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.323C>A	p.Thr108Asn	missense	Exon 3 of 6	NP_001309395.1	Q5TD97
	FHL5	NM_001170807.3		c.323C>A	p.Thr108Asn	missense	Exon 3 of 6	NP_001164278.1	Q5TD97
	FHL5	NM_001322467.1		c.323C>A	p.Thr108Asn	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.323C>A	p.Thr108Asn	missense	Exon 3 of 6	ENSP00000396390.2	Q5TD97
	FHL5	ENST00000326771.2	TSL:1	c.323C>A	p.Thr108Asn	missense	Exon 4 of 7	ENSP00000326022.2	Q5TD97
	FHL5	ENST00000541107.5	TSL:1	c.323C>A	p.Thr108Asn	missense	Exon 3 of 6	ENSP00000442357.1	Q5TD97

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000245 AC: 6 AN: 244664 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1453744 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4 AN XY: 722698

African (AFR) AF: 0.00 AC: 0 AN: 33160

American (AMR) AF: 0.00 AC: 0 AN: 43954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39376

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107524

Other (OTH) AF: 0.0000167 AC: 1 AN: 60048

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.013	D
Sift4G	Benign	0.32	T
Polyphen		0.12	B
Vest4		0.27
MutPred		0.35		Gain of relative solvent accessibility (P = 0.1066)
MVP		0.89
MPC		0.034
ClinPred		0.40	T
GERP RS		4.4
Varity_R		0.34
gMVP		0.50
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs540080032; hg19: chr6-97052789;