6-96610726-A-G

Variant names:

• chr6-96610726-A-G
• NM_001322466.2:c.659A>G

Variant summary

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

The NM_001322466.2(FHL5):​c.659A>G​(p.Asn220Ser) 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. 14/21 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: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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=0.18790111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL5	NM_001322466.2	c.659A>G	p.Asn220Ser	missense_variant	Exon 5 of 6	ENST00000450218.6	NP_001309395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL5	ENST00000450218.6	c.659A>G	p.Asn220Ser	missense_variant	Exon 5 of 6	5	NM_001322466.2	ENSP00000396390.2
FHL5	ENST00000326771.2	c.659A>G	p.Asn220Ser	missense_variant	Exon 6 of 7	1		ENSP00000326022.2
FHL5	ENST00000541107.5	c.659A>G	p.Asn220Ser	missense_variant	Exon 5 of 6	1		ENSP00000442357.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.659A>G (p.N220S) alteration is located in exon 6 (coding exon 4) of the FHL5 gene. This alteration results from a A to G substitution at nucleotide position 659, causing the asparagine (N) at amino acid position 220 to be replaced by a serine (S). 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	0.066
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T;.
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.81	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.0	B;B
Vest4		0.14
MutPred		0.57		Loss of stability (P = 0.0306);Loss of stability (P = 0.0306);
MVP		0.60
MPC		0.027
ClinPred		0.75	D
GERP RS		4.8
Varity_R		0.068
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-97058602; COSMIC: COSV105888404; COSMIC: COSV105888404;