Genetic Variant FMNL1:c.895-3C>T (chr17-45238561-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_005892.4(FMNL1):c.895-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 1,614,108 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 66 hom. )

Consequence

FMNL1
NM_005892.4 splice_region, intron

Scores

Splicing: ADA: 0.1549

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.81

Variant links:

Genes affected

FMNL1 (HGNC:1212): (formin like 1) This gene encodes a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity. An alternative splice variant has been described but its full length sequence has not been determined. [provided by RefSeq, Jul 2008]

FMNL1 links:

FMNL1-AS1 (HGNC:55717): (FMNL1 antisense RNA 1)

FMNL1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

BP6

Variant 17-45238561-C-T is Benign according to our data. Variant chr17-45238561-C-T is described in ClinVar as [Benign]. Clinvar id is 775325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00585 (8554/1461776) while in subpopulation MID AF= 0.0352 (203/5764). AF 95% confidence interval is 0.0313. There are 66 homozygotes in gnomad4_exome. There are 4528 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 713 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
FMNL1	NM_005892.4 link	c.895-3C>T	splice_region_variant, intron_variant	Intron 9 of 26	ENST00000331495.8	NP_005883.3	O95466-1
FMNL1	NM_001411128.1 link	c.895-3C>T	splice_region_variant, intron_variant	Intron 9 of 25		NP_001398057.1
FMNL1-AS1	NR_186807.1 link	n.1506G>A	non_coding_transcript_exon_variant	Exon 2 of 2
FMNL1-AS1	NR_186808.1 link	n.1456G>A	non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMNL1	ENST00000331495.8 link	c.895-3C>T		splice_region_variant, intron_variant	Intron 9 of 26	1	NM_005892.4	ENSP00000329219.2		O95466-1

Frequencies

GnomAD3 genomes

AF:

0.00469

AC:

714

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.0389

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00506

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.00703

AC:

1767

AN:

251370

Hom.:

AF XY:

0.00780

AC XY:

1060

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.0368

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0143

Gnomad FIN exome

AF:

0.00374

Gnomad NFE exome

AF:

0.00616

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00585

AC:

8554

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

4528

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00288

Gnomad4 ASJ exome

AF:

0.0359

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0145

Gnomad4 FIN exome

AF:

0.00373

Gnomad4 NFE exome

AF:

0.00475

Gnomad4 OTH exome

AF:

0.00853

GnomAD4 genome

AF:

0.00468

AC:

713

AN:

152332

Hom.:

Cov.:

AF XY:

0.00489

AC XY:

364

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.0389

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0166

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.00506

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00729

Hom.:

Bravo

AF:

0.00407

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00638

EpiControl

AF:

0.00640

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.15

dbscSNV1_RF

Benign

0.19

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over