15-43873170-C-T

Variant names:

• chr15-43873170-C-T
• rs146884659
• NM_032892.5:c.*715G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001322949.2(FRMD5):​c.1531+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,549,868 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (28 hom.)
• Consequence: FRMD5 NM_001322949.2 splice_donor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.45
• Publications: 1 publications found

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]

FRMD5 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with eye movement abnormalities and ataxia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005738586).
• BP6: Variant 15-43873170-C-T is Benign according to our data. Variant chr15-43873170-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3352706.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 557 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322949.2. 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
	FRMD5	NM_032892.5	MANE Select	c.*715G>A		3_prime_UTR	Exon 14 of 14	NP_116281.2	Q7Z6J6-1
	FRMD5	NM_001411124.1		c.1532G>A	p.Gly511Asp	missense	Exon 15 of 15	NP_001398053.1	B5MC67
	FRMD5	NM_001322950.2		c.*722G>A		3_prime_UTR	Exon 15 of 15	NP_001309879.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD5	ENST00000417257.6	TSL:1 MANE Select	c.*715G>A		3_prime_UTR	Exon 14 of 14	ENSP00000403067.1	Q7Z6J6-1
	FRMD5	ENST00000402883.5	TSL:5	c.1532G>A	p.Gly511Asp	missense	Exon 15 of 15	ENSP00000384142.1	B5MC67
	FRMD5	ENST00000618556.4	TSL:5	c.*715G>A		3_prime_UTR	Exon 14 of 14	ENSP00000479575.1	A0A087WVP2

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 559 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00573

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00364 AC: 542 AN: 149052 AF XY: 0.00375

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00346

Gnomad ASJ exome AF: 0.00657

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000595

Gnomad NFE exome AF: 0.00603

Gnomad OTH exome AF: 0.00557

GnomAD4 exome AF: 0.00523 AC: 7312 AN: 1397584 Hom.: 28 Cov.: 31 AF XY: 0.00516 AC XY: 3557 AN XY: 689344

African (AFR) AF: 0.000982 AC: 31 AN: 31584

American (AMR) AF: 0.00367 AC: 131 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00516 AC: 130 AN: 25180

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35734

South Asian (SAS) AF: 0.00163 AC: 129 AN: 79216

European-Finnish (FIN) AF: 0.000187 AC: 9 AN: 48160

Middle Eastern (MID) AF: 0.0137 AC: 78 AN: 5698

European-Non Finnish (NFE) AF: 0.00600 AC: 6465 AN: 1078340

Other (OTH) AF: 0.00583 AC: 338 AN: 57968

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00332 AC XY: 247 AN XY: 74466

African (AFR) AF: 0.000770 AC: 32 AN: 41552

American (AMR) AF: 0.00589 AC: 90 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00573 AC: 390 AN: 68030

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00377 Hom.: 3

Bravo AF: 0.00400

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ExAC AF: 0.00211 AC: 43

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	FRMD5-related condition (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0049	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.39	T
PhyloP100		2.5
PROVEAN	Benign	0.15	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.18
MVP		0.56
ClinPred		0.055	T
GERP RS		3.1
Mutation Taster		=91/9	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: rs146884659; hg19: chr15-44165368; COSMIC: COSV99028000; COSMIC: COSV99028000;