NM_031471.6:c.1506C>T

Variant names:

• chr11-64220630-C-T
• rs3802933
• NM_031471.6:c.1506C>T

Variant summary

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

The NM_031471.6(FERMT3):​c.1506C>T​(p.Leu502Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,610,504 control chromosomes in the GnomAD database, including 24,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2479 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22422 hom.)
• Consequence: FERMT3 NM_031471.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.38
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011279881).
• BP6: Variant 11-64220630-C-T is Benign according to our data. Variant chr11-64220630-C-T is described in ClinVar as Benign. ClinVar VariationId is 402864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.276 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.1506C>T	p.Leu502Leu	synonymous	Exon 12 of 15	NP_113659.3
	FERMT3	NM_001382362.1		c.1518C>T	p.Leu506Leu	synonymous	Exon 12 of 15	NP_001369291.1	Q86UX7-1
	FERMT3	NM_178443.3		c.1518C>T	p.Leu506Leu	synonymous	Exon 12 of 15	NP_848537.1	Q86UX7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FERMT3	ENST00000345728.10	TSL:1 MANE Select	c.1506C>T	p.Leu502Leu	synonymous	Exon 12 of 15	ENSP00000339950.5	Q86UX7-2
	FERMT3	ENST00000279227.10	TSL:1	c.1518C>T	p.Leu506Leu	synonymous	Exon 12 of 15	ENSP00000279227.5	Q86UX7-1
	FERMT3	ENST00000698865.1		c.1527C>T	p.Leu509Leu	synonymous	Exon 12 of 15	ENSP00000513992.1	A0A8V8TP41

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26416 AN: 152106 Hom.: 2473 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.0887

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.179 AC: 43003 AN: 240268 AF XY: 0.173

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.185

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.172 AC: 250099 AN: 1458280 Hom.: 22422 Cov.: 35 AF XY: 0.169 AC XY: 122748 AN XY: 725280

African (AFR) AF: 0.140 AC: 4672 AN: 33428

American (AMR) AF: 0.307 AC: 13603 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4627 AN: 26030

East Asian (EAS) AF: 0.184 AC: 7271 AN: 39582

South Asian (SAS) AF: 0.0965 AC: 8289 AN: 85898

European-Finnish (FIN) AF: 0.170 AC: 8855 AN: 52184

Middle Eastern (MID) AF: 0.190 AC: 1095 AN: 5764

European-Non Finnish (NFE) AF: 0.172 AC: 190715 AN: 1110854

Other (OTH) AF: 0.182 AC: 10972 AN: 60288

GnomAD4 genome AF: 0.174 AC: 26448 AN: 152224 Hom.: 2479 Cov.: 33 AF XY: 0.175 AC XY: 13044 AN XY: 74424

African (AFR) AF: 0.142 AC: 5879 AN: 41542

American (AMR) AF: 0.283 AC: 4323 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 609 AN: 3472

East Asian (EAS) AF: 0.187 AC: 970 AN: 5174

South Asian (SAS) AF: 0.0890 AC: 430 AN: 4830

European-Finnish (FIN) AF: 0.175 AC: 1853 AN: 10606

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11782 AN: 67988

Other (OTH) AF: 0.204 AC: 430 AN: 2108

Alfa AF: 0.171 Hom.: 1320

Bravo AF: 0.182

TwinsUK AF: 0.172 AC: 639

ALSPAC AF: 0.167 AC: 643

ESP6500AA AF: 0.137 AC: 601

ESP6500EA AF: 0.170 AC: 1457

ExAC AF: 0.167 AC: 20227

Asia WGS AF: 0.156 AC: 541 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Leukocyte adhesion deficiency 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.94
DANN	Benign	0.90
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.4
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.0090
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.055	T
ClinPred		0.010	T
GERP RS		-8.4
PromoterAI		0.0058	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3802933; hg19: chr11-63988102; COSMIC: COSV54180771; COSMIC: COSV54180771;