NM_001322466.2:c.38C>T

Variant names:

• chr6-96603651-C-T
• rs370135459
• NM_001322466.2:c.38C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001322466.2(FHL5):​c.38C>T​(p.Ala13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: FHL5 NM_001322466.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12859443).

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.38C>T	p.Ala13Val	missense	Exon 2 of 6	NP_001309395.1	Q5TD97
	FHL5	NM_001170807.3		c.38C>T	p.Ala13Val	missense	Exon 2 of 6	NP_001164278.1	Q5TD97
	FHL5	NM_001322467.1		c.38C>T	p.Ala13Val	missense	Exon 3 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.38C>T	p.Ala13Val	missense	Exon 2 of 6	ENSP00000396390.2	Q5TD97
	FHL5	ENST00000326771.2	TSL:1	c.38C>T	p.Ala13Val	missense	Exon 3 of 7	ENSP00000326022.2	Q5TD97
	FHL5	ENST00000541107.5	TSL:1	c.38C>T	p.Ala13Val	missense	Exon 2 of 6	ENSP00000442357.1	Q5TD97

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000160 AC: 4 AN: 250606 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000291

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: 0.0000199 AC: 29 AN: 1460714 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726678

African (AFR) AF: 0.000568 AC: 19 AN: 33452

American (AMR) AF: 0.0000448 AC: 2 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111494

Other (OTH) AF: 0.0000829 AC: 5 AN: 60344

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74340

African (AFR) AF: 0.000193 AC: 8 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000988 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

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	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Benign	0.070	T
Sift4G	Uncertain	0.031	D
Polyphen		0.0010	B
Vest4		0.15
MVP		0.82
MPC		0.030
ClinPred		0.092	T
GERP RS		3.6
Varity_R		0.079
gMVP		0.13
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs370135459; hg19: chr6-97051527;