15-43873961-T-C

Position:

• chr15-43873961-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032892.5(FRMD5):​c.1637A>G​(p.Tyr546Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FRMD5 NM_032892.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.84

Genes affected

FRMD5 (HGNC:28214): (FERM domain containing 5) Enables integrin binding activity and protein kinase binding activity. Involved in negative regulation of cell motility; positive regulation of cell adhesion; and regulation of cell migration. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD5	NM_032892.5	c.1637A>G	p.Tyr546Cys	missense_variant	14/14	ENST00000417257.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD5	ENST00000417257.6	c.1637A>G	p.Tyr546Cys	missense_variant	14/14	1	NM_032892.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with eye movement abnormalities and ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 27, 2022

- -

Neurodevelopmental delay Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.48	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
Sift4G	Uncertain	0.0050	D;T;.
Polyphen		1.0	.;D;.
Vest4		0.70
MutPred		0.68		.;Gain of helix (P = 0.062);.;
MVP		0.63
MPC		0.37
ClinPred		0.99	D
GERP RS		5.8
La Branchor		0.69
Varity_R		0.25
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs1006096376; hg19: chr15-44166159;