20-6116048-C-T

Variant names:

• chr20-6116048-C-T
• rs2295435
• NM_017671.5:c.152-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017671.5(FERMT1):​c.152-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,605,506 control chromosomes in the GnomAD database, including 147,737 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 0.40 (12729 hom., cov: 32)
  • Exomes 𝑓: 0.43 (135008 hom.)
• Consequence: FERMT1 NM_017671.5 splice_region, intron
• Scores: Splicing: ADA: 0.0002425
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.526
• Publications: 14 publications found

Genes affected

FERMT1 (HGNC:15889): (FERM domain containing kindlin 1) This gene encodes a member of the fermitin family, and contains a FERM domain and a pleckstrin homology domain. The encoded protein is involved in integrin signaling and linkage of the actin cytoskeleton to the extracellular matrix. Mutations in this gene have been linked to Kindler syndrome. [provided by RefSeq, Dec 2009]

FERMT1 Gene-Disease associations (from GenCC):

• Kindler syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 20-6116048-C-T is Benign according to our data. Variant chr20-6116048-C-T is described in ClinVar as Benign. ClinVar VariationId is 260865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017671.5. 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
	FERMT1	NM_017671.5	MANE Select	c.152-4G>A		splice_region intron	N/A	NP_060141.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT1	ENST00000217289.9	TSL:1 MANE Select	c.152-4G>A		splice_region intron	N/A	ENSP00000217289.4	Q9BQL6-1
	FERMT1	ENST00000536936.1	TSL:1	n.135-4G>A		splice_region intron	N/A	ENSP00000441063.2	G3V1L6
	FERMT1	ENST00000699095.1		c.152-4G>A		splice_region intron	N/A	ENSP00000514127.1	Q9BQL6-1

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61477 AN: 151830 Hom.: 12730 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.452

GnomAD2 exomes AF: 0.426 AC: 104442 AN: 245012 AF XY: 0.439

Gnomad AFR exome AF: 0.362

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.296

Gnomad FIN exome AF: 0.322

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.427 AC: 620495 AN: 1453556 Hom.: 135008 Cov.: 29 AF XY: 0.432 AC XY: 312703 AN XY: 723598

African (AFR) AF: 0.365 AC: 12167 AN: 33300

American (AMR) AF: 0.398 AC: 17710 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 13821 AN: 26056

East Asian (EAS) AF: 0.304 AC: 12045 AN: 39636

South Asian (SAS) AF: 0.579 AC: 49789 AN: 86052

European-Finnish (FIN) AF: 0.329 AC: 17499 AN: 53232

Middle Eastern (MID) AF: 0.544 AC: 3131 AN: 5752

European-Non Finnish (NFE) AF: 0.424 AC: 468815 AN: 1104956

Other (OTH) AF: 0.425 AC: 25518 AN: 60100

GnomAD4 genome AF: 0.405 AC: 61482 AN: 151950 Hom.: 12729 Cov.: 32 AF XY: 0.402 AC XY: 29866 AN XY: 74282

African (AFR) AF: 0.366 AC: 15158 AN: 41432

American (AMR) AF: 0.415 AC: 6336 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1855 AN: 3472

East Asian (EAS) AF: 0.302 AC: 1558 AN: 5156

South Asian (SAS) AF: 0.581 AC: 2794 AN: 4810

European-Finnish (FIN) AF: 0.313 AC: 3300 AN: 10556

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28935 AN: 67950

Other (OTH) AF: 0.446 AC: 940 AN: 2108

Alfa AF: 0.423 Hom.: 49573

Bravo AF: 0.407

Asia WGS AF: 0.407 AC: 1417 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Kindler syndrome (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.1
DANN	Benign	0.68
PhyloP100		0.53
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.0060
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: rs2295435; hg19: chr20-6096695; COSMIC: COSV54091784;