9-83389643-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_174938.6(FRMD3):c.213C>A(p.Asp71Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRMD3 NM_174938.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.70

Genes affected

FRMD3 (HGNC:24125): (FERM domain containing 3) The protein encoded by this gene is a single pass membrane protein primarily found in ovaries. A similar protein in erythrocytes helps determine the shape of red blood cells, but the function of the encoded protein has not been determined. There is some evidence that this is a tumor suppressor gene, and there is also evidence linking defects in this gene to susceptibility to diabetic nephropathy in type 1 diabetes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD3	NM_174938.6	c.213C>A	p.Asp71Glu	missense_variant	2/14	ENST00000304195.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD3	ENST00000304195.8	c.213C>A	p.Asp71Glu	missense_variant	2/14	1	NM_174938.6	P1
FRMD3	ENST00000621208.4	c.81C>A	p.Asp27Glu	missense_variant	2/14	1
FRMD3	ENST00000376438.5	c.213C>A	p.Asp71Glu	missense_variant	2/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.213C>A (p.D71E) alteration is located in exon 1 (coding exon 1) of the FRMD3 gene. This alteration results from a C to A substitution at nucleotide position 213, causing the aspartic acid (D) at amino acid position 71 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	-0.047	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.2	D;D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.025	D;D;.
Sift4G	Uncertain	0.039	D;T;T
Polyphen		0.99	D;D;.
Vest4		0.88
MutPred		0.88		Gain of methylation at K70 (P = 0.0908);Gain of methylation at K70 (P = 0.0908);.;
MVP		0.76
MPC		0.69
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.72
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-86004558;