chr6-168060793-C-T

Variant names:

• chr6-168060793-C-T
• rs753945376
• NM_024919.6:c.1310G>A

Variant summary

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

The NM_024919.6(FRMD1):​c.1310G>A​(p.Arg437His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,611,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: FRMD1 NM_024919.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.208
• Publications: 0 publications found

Genes affected

FRMD1 (HGNC:21240): (FERM domain containing 1) Predicted to be involved in positive regulation of hippo signaling. Predicted to be located in cytoskeleton. Predicted to be active in cytoplasmic side of apical plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.03200513).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024919.6. 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
	FRMD1	NM_024919.6	MANE Select	c.1310G>A	p.Arg437His	missense	Exon 9 of 11	NP_079195.3
	FRMD1	NM_001394681.1		c.1115G>A	p.Arg372His	missense	Exon 8 of 10	NP_001381610.1	A0A2R8Y6M2
	FRMD1	NM_001122841.3		c.1106G>A	p.Arg369His	missense	Exon 9 of 11	NP_001116313.1	Q8N878-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRMD1	ENST00000283309.11	TSL:1 MANE Select	c.1310G>A	p.Arg437His	missense	Exon 9 of 11	ENSP00000283309.6	Q8N878-1
	FRMD1	ENST00000432403.5	TSL:1	n.997G>A		non_coding_transcript_exon	Exon 7 of 9
	FRMD1	ENST00000646385.1		c.1505G>A	p.Arg502His	missense	Exon 12 of 14	ENSP00000494166.1	A0A2R8Y4L9

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249144 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1459574 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 725796

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110610

Other (OTH) AF: 0.0000166 AC: 1 AN: 60272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000463383), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74472

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000709 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.36
DANN	Benign	0.94
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.060	N
PhyloP100		-0.21
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.016
Sift	Benign	0.56	T
Sift4G	Benign	0.36	T
Polyphen		0.040	B
Vest4		0.088
MVP		0.26
MPC		0.13
ClinPred		0.037	T
GERP RS		-5.0
Varity_R		0.017
gMVP		0.089
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs753945376; hg19: chr6-168461473; COSMIC: COSV51960648; COSMIC: COSV51960648;