1-37998115-A-G

Variant names:

• chr1-37998115-A-G
• rs1401808494
• NM_004468.5:c.349T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004468.5(FHL3):​c.349T>C​(p.Tyr117His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FHL3 NM_004468.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25

Genes affected

FHL3 (HGNC:3704): (four and a half LIM domains 3) The protein encoded by this gene is a member of a family of proteins containing a four-and-a-half LIM domain, which is a highly conserved double zinc finger motif. The encoded protein has been shown to interact with the cancer developmental regulators SMAD2, SMAD3, and SMAD4, the skeletal muscle myogenesis protein MyoD, and the high-affinity IgE beta chain regulator MZF-1. This protein may be involved in tumor suppression, repression of MyoD expression, and repression of IgE receptor expression. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL3	NM_004468.5	c.349T>C	p.Tyr117His	missense_variant	Exon 4 of 6	ENST00000373016.4	NP_004459.2
FHL3	NM_001243878.2	c.25T>C	p.Tyr9His	missense_variant	Exon 3 of 5		NP_001230807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL3	ENST00000373016.4	c.349T>C	p.Tyr117His	missense_variant	Exon 4 of 6	1	NM_004468.5	ENSP00000362107.3
FHL3	ENST00000485803.5	n.339T>C		non_coding_transcript_exon_variant	Exon 3 of 5	1
FHL3	ENST00000477194.5	n.537T>C		non_coding_transcript_exon_variant	Exon 4 of 6	2
FHL3	ENST00000475084.5	n.322-245T>C		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.349T>C (p.Y117H) alteration is located in exon 4 (coding exon 3) of the FHL3 gene. This alteration results from a T to C substitution at nucleotide position 349, causing the tyrosine (Y) at amino acid position 117 to be replaced by a histidine (H). 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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.79
Sift	Benign	0.046	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.59		Gain of disorder (P = 0.0174);
MVP		0.85
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.55
gMVP		0.63

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: rs1401808494; hg19: chr1-38463787;