chr11-64219867-C-T

Variant names:

• chr11-64219867-C-T
• rs11231726
• NM_031471.6:c.1080-24C>T

Variant summary

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

The NM_031471.6(FERMT3):​c.1080-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,613,730 control chromosomes in the GnomAD database, including 19,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.11 (1164 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17908 hom.)
• Consequence: FERMT3 NM_031471.6 intron
• Scores: Splicing: ADA: 0.0009682
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.280
• Publications: 12 publications found

Genes affected

FERMT3 (HGNC:23151): (FERM domain containing kindlin 3) Kindlins are a small family of proteins that mediate protein-protein interactions involved in integrin activation and thereby have a role in cell adhesion, migration, differentiation, and proliferation. The protein encoded by this gene has a key role in the regulation of hemostasis and thrombosis. This protein may also help maintain the membrane skeleton of erythrocytes. Mutations in this gene cause the autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2010]

FERMT3 Gene-Disease associations (from GenCC):

• leukocyte adhesion deficiency 3

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

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-64219867-C-T is Benign according to our data. Variant chr11-64219867-C-T is described in ClinVar as Benign. ClinVar VariationId is 402863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031471.6. 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
	FERMT3	NM_031471.6	MANE Select	c.1080-24C>T		intron	N/A	NP_113659.3
	FERMT3	NM_001382362.1		c.1080-12C>T		intron	N/A	NP_001369291.1
	FERMT3	NM_178443.3		c.1080-12C>T		intron	N/A	NP_848537.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	ENST00000345728.10	TSL:1 MANE Select	c.1080-24C>T		intron	N/A	ENSP00000339950.5
	FERMT3	ENST00000279227.10	TSL:1	c.1080-12C>T		intron	N/A	ENSP00000279227.5
	FERMT3	ENST00000698865.1		c.1101-24C>T		intron	N/A	ENSP00000513992.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16842 AN: 152046 Hom.: 1164 Cov.: 32

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.0888

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.0764

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.118 AC: 29489 AN: 250840 AF XY: 0.119

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.0848

Gnomad ASJ exome AF: 0.0715

Gnomad EAS exome AF: 0.0870

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.151 AC: 221350 AN: 1461566 Hom.: 17908 Cov.: 37 AF XY: 0.149 AC XY: 108381 AN XY: 727090

African (AFR) AF: 0.0396 AC: 1327 AN: 33480

American (AMR) AF: 0.0855 AC: 3826 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 1852 AN: 26134

East Asian (EAS) AF: 0.126 AC: 4999 AN: 39696

South Asian (SAS) AF: 0.0750 AC: 6469 AN: 86256

European-Finnish (FIN) AF: 0.127 AC: 6742 AN: 53128

Middle Eastern (MID) AF: 0.0586 AC: 338 AN: 5768

European-Non Finnish (NFE) AF: 0.169 AC: 187910 AN: 1111990

Other (OTH) AF: 0.131 AC: 7887 AN: 60390

GnomAD4 genome AF: 0.111 AC: 16849 AN: 152164 Hom.: 1164 Cov.: 32 AF XY: 0.108 AC XY: 8010 AN XY: 74384

African (AFR) AF: 0.0440 AC: 1825 AN: 41520

American (AMR) AF: 0.0889 AC: 1359 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 264 AN: 3468

East Asian (EAS) AF: 0.0944 AC: 488 AN: 5170

South Asian (SAS) AF: 0.0769 AC: 371 AN: 4824

European-Finnish (FIN) AF: 0.114 AC: 1205 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10974 AN: 67966

Other (OTH) AF: 0.0990 AC: 209 AN: 2112

Alfa AF: 0.123 Hom.: 314

Bravo AF: 0.107

Asia WGS AF: 0.0840 AC: 293 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.9
DANN	Benign	0.75
PhyloP100		0.28
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00097
dbscSNV1_RF	Benign	0.036
SpliceAI score (max)		0.050		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: rs11231726; hg19: chr11-63987339; COSMIC: COSV54181615; COSMIC: COSV54181615;