X-77454272-G-GTTT

Variant names:

• chrX-77454272-G-GTTT
• rs782034788
• NM_003868.3:c.378+40_378+42dupTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_003868.3(FGF16):​c.378+40_378+42dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (18 hom., 13 hem., cov: 11)
  • Exomes 𝑓: 0.025 (0 hom. 17 hem.)
  • Failed GnomAD Quality Control
• Consequence: FGF16 NM_003868.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.691
• Publications: 0 publications found

Genes affected

FGF16 (HGNC:3672): (fibroblast growth factor 16) This gene encodes a member of a family of proteins that are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene is expressed in cardiac cells and is required for proper heart development. Mutation in this gene was also observed in individuals with metacarpal 4-5 fusion. [provided by RefSeq, Mar 2014]

FGF16 Gene-Disease associations (from GenCC):

• syndactyly type 8

  Inheritance: AD, XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000295984 (HGNC:):

ACMG classification

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

• BP6: Variant X-77454272-G-GTTT is Benign according to our data. Variant chrX-77454272-G-GTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 1194154.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003868.3. 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
	FGF16	NM_003868.3	MANE Select	c.378+40_378+42dupTTT		intron	N/A	NP_003859.1	O43320

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF16	ENST00000439435.3	TSL:1 MANE Select	c.378+12_378+13insTTT		intron	N/A	ENSP00000399324.2	O43320
	ENSG00000295984	ENST00000734738.1		n.179+6933_179+6934insAAA		intron	N/A
	ENSG00000295984	ENST00000734739.1		n.45+6933_45+6934insAAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 276 AN: 45892 Hom.: 18 Cov.: 11

Gnomad AFR AF: 0.00623

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00210

Gnomad EAS AF: 0.00166

Gnomad SAS AF: 0.00185

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00679

Gnomad OTH AF: 0.00877

GnomAD2 exomes AF: 0.00869 AC: 206 AN: 23700 AF XY: 0.00

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.00892

Gnomad EAS exome AF: 0.0246

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00633

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.0250 AC: 2568 AN: 102787 Hom.: 0 Cov.: 5 AF XY: 0.000609 AC XY: 17 AN XY: 27933

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

African (AFR) AF: 0.0423 AC: 63 AN: 1491

American (AMR) AF: 0.0239 AC: 79 AN: 3304

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 61 AN: 2911

East Asian (EAS) AF: 0.0229 AC: 51 AN: 2229

South Asian (SAS) AF: 0.0206 AC: 262 AN: 12743

European-Finnish (FIN) AF: 0.0126 AC: 188 AN: 14932

Middle Eastern (MID) AF: 0.0197 AC: 9 AN: 457

European-Non Finnish (NFE) AF: 0.0288 AC: 1724 AN: 59849

Other (OTH) AF: 0.0269 AC: 131 AN: 4871

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00601 AC: 276 AN: 45887 Hom.: 18 Cov.: 11 AF XY: 0.00143 AC XY: 13 AN XY: 9083

African (AFR) AF: 0.00623 AC: 62 AN: 9953

American (AMR) AF: 0.00465 AC: 17 AN: 3654

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 3 AN: 1428

East Asian (EAS) AF: 0.00167 AC: 2 AN: 1198

South Asian (SAS) AF: 0.00183 AC: 1 AN: 545

European-Finnish (FIN) AF: 0.00254 AC: 3 AN: 1179

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 58

European-Non Finnish (NFE) AF: 0.00679 AC: 183 AN: 26937

Other (OTH) AF: 0.00876 AC: 5 AN: 571

Alfa AF: 0.00331 Hom.: 186

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs782034788; hg19: chrX-76709763;