NM_017671.5:c.114T>C

Variant names:

• chr20-6119441-A-G
• rs10373
• NM_017671.5:c.114T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017671.5(FERMT1):​c.114T>C​(p.His38His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,613,046 control chromosomes in the GnomAD database, including 226,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20867 hom., cov: 33)
  • Exomes 𝑓: 0.53 (205547 hom.)
• Consequence: FERMT1 NM_017671.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.140
• Publications: 28 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-6119441-A-G is Benign according to our data. Variant chr20-6119441-A-G is described in ClinVar as Benign. ClinVar VariationId is 260864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.623 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT1	NM_017671.5	MANE Select	c.114T>C	p.His38His	synonymous	Exon 2 of 15	NP_060141.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT1	ENST00000217289.9	TSL:1 MANE Select	c.114T>C	p.His38His	synonymous	Exon 2 of 15	ENSP00000217289.4
	FERMT1	ENST00000536936.1	TSL:1	n.114T>C		non_coding_transcript_exon	Exon 2 of 14	ENSP00000441063.2
	FERMT1	ENST00000699095.1		c.114T>C	p.His38His	synonymous	Exon 1 of 14	ENSP00000514127.1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79162 AN: 151960 Hom.: 20867 Cov.: 33

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.520 AC: 130603 AN: 251378 AF XY: 0.530

Gnomad AFR exome AF: 0.534

Gnomad AMR exome AF: 0.463

Gnomad ASJ exome AF: 0.613

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.529

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.527 AC: 770633 AN: 1460972 Hom.: 205547 Cov.: 42 AF XY: 0.532 AC XY: 386474 AN XY: 726796

African (AFR) AF: 0.544 AC: 18191 AN: 33462

American (AMR) AF: 0.465 AC: 20789 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 15987 AN: 26132

East Asian (EAS) AF: 0.374 AC: 14856 AN: 39672

South Asian (SAS) AF: 0.652 AC: 56233 AN: 86250

European-Finnish (FIN) AF: 0.424 AC: 22645 AN: 53396

Middle Eastern (MID) AF: 0.618 AC: 3560 AN: 5764

European-Non Finnish (NFE) AF: 0.528 AC: 586444 AN: 1111206

Other (OTH) AF: 0.529 AC: 31928 AN: 60366

GnomAD4 genome AF: 0.521 AC: 79180 AN: 152074 Hom.: 20867 Cov.: 33 AF XY: 0.516 AC XY: 38382 AN XY: 74332

African (AFR) AF: 0.536 AC: 22247 AN: 41490

American (AMR) AF: 0.496 AC: 7582 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2118 AN: 3472

East Asian (EAS) AF: 0.380 AC: 1959 AN: 5154

South Asian (SAS) AF: 0.642 AC: 3092 AN: 4818

European-Finnish (FIN) AF: 0.414 AC: 4380 AN: 10572

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35960 AN: 67966

Other (OTH) AF: 0.538 AC: 1134 AN: 2108

Alfa AF: 0.531 Hom.: 35213

Bravo AF: 0.524

Asia WGS AF: 0.471 AC: 1641 AN: 3478

EpiCase AF: 0.538

EpiControl AF: 0.549

ClinVar

ClinVar submissions as Germline

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	-0.82
CADD	Benign	2.4
DANN	Benign	0.38
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs10373; hg19: chr20-6100088; COSMIC: COSV54091799;