rs1785637721

Variant names:

• chr9-83290635-C-G
• rs1785637721
• NM_174938.6:c.1163G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_174938.6(FRMD3):​c.1163G>C​(p.Ser388Thr) 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 benign outcome for this variant. 17/22 in silico tools predict a benign 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: -0.168
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031044543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD3	NM_174938.6	c.1163G>C	p.Ser388Thr	missense_variant	Exon 13 of 14	ENST00000304195.8	NP_777598.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD3	ENST00000304195.8	c.1163G>C	p.Ser388Thr	missense_variant	Exon 13 of 14	1	NM_174938.6	ENSP00000303508.3
FRMD3	ENST00000621208.4	c.1031G>C	p.Ser344Thr	missense_variant	Exon 13 of 14	1		ENSP00000484839.1
FRMD3	ENST00000376434.5	c.581G>C	p.Ser194Thr	missense_variant	Exon 8 of 10	1		ENSP00000365617.1
FRMD3	ENST00000376438.5	c.1163G>C	p.Ser388Thr	missense_variant	Exon 13 of 15	2		ENSP00000365621.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1163G>C (p.S388T) alteration is located in exon 1 (coding exon 1) of the FRMD3 gene. This alteration results from a G to C substitution at nucleotide position 1163, causing the serine (S) at amino acid position 388 to be replaced by a threonine (T). 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	Benign	0.058
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.7
DANN	Benign	0.77
DEOGEN2	Benign	0.0048	.;.;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.58	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.031	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.69	.;N;N;.
PhyloP100		-0.17
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.29	N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.81	T;T;T;.
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.15
MutPred		0.21		.;Gain of glycosylation at S388 (P = 0.0273);Gain of glycosylation at S388 (P = 0.0273);.;
MVP		0.57
MPC		0.16
ClinPred		0.44	T
GERP RS		0.53
Varity_R		0.047
gMVP		0.22
Mutation Taster		=95/5	polymorphism

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: rs1785637721; hg19: chr9-85905550;