9-41127338-C-T

Variant names:

• chr9-41127338-C-T
• rs79840213
• NM_001085476.4:c.1046G>A

Variant summary

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

The NM_001085476.4(FOXD4L6):​c.1046G>A​(p.Arg349His) 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. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000096 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXD4L6 NM_001085476.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.97
• Publications: 1 publications found

Genes affected

FOXD4L6 (HGNC:31986): (forkhead box D4 like 6) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anatomical structure morphogenesis; cell differentiation; and regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

FRG1HP (HGNC:51767): (FSHD region gene 1 family member H, pseudogene)

ENSG00000308937 (HGNC:):

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=0.052737296).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085476.4. 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
	FOXD4L6	NM_001085476.4	MANE Select	c.1046G>A	p.Arg349His	missense	Exon 1 of 1	NP_001078945.1	Q3SYB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4L6	ENST00000622588.2	TSL:6 MANE Select	c.1046G>A	p.Arg349His	missense	Exon 1 of 1	ENSP00000484875.1	Q3SYB3
	FRG1HP	ENST00000617940.2	TSL:6	n.412-67763C>T		intron	N/A
	ENSG00000308937	ENST00000837379.1		n.683+1700C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000959 AC: 14 AN: 1459630 Hom.: 0 Cov.: 36 AF XY: 0.00000964 AC XY: 7 AN XY: 726116

⚠️ 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: 33404

American (AMR) AF: 0.0000447 AC: 2 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53414

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4134

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111774

Other (OTH) AF: 0.0000166 AC: 1 AN: 60206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.11
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.82
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0082	T
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.053	T
PhyloP100		-4.0
Sift4G	Benign	0.46	T
Vest4		0.073
gMVP		0.029

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: rs79840213; hg19: chr9-70918913;